Msc Organic reaction mechanism and reaction

Organic Reaction Mechanism
amaresh.mishra@suniv.ac.in
Amaresh Mishra
School of Chemistry
Sambalpur University
Jyoti Vihar
1

1 Introduction
2 Types of Addition Reaction
1. Electrophilic, Nucleophilic and Free Radical Addition
2. Addition to Carbon-Carbon Multiple Bonds
3. Addition to Carbon-heteroatom Multiple Bonds
4. Addition to Conjugated System
3 Mechanism, Reactivity and Stereochemical Aspects
4 Reactions
4.1 Epoxidation
4.2 Hydroboration
4.3 Addition to Cyclopropanes
4.4 Name Reactions
5. References
2

In a chemical reaction one reactant acts as nucleophile and
another acts as an electrophile
3
 The curly arrow moved from nucleophile to the electrophile
 The nucleophile has given away electrons so it has become
positively charged and
 the electrophile has accepted electrons so it has become neutral.

Type of Nucleophiles
4
 In cyanide the anionic carbon usually acts as nucleophile rather than
neutral nitrogen as the sp orbital on carbon has a higher energy than that
on the more electronegative nitrogen.
 σ bonds of BH4
- ion act as nucleophiles
 The borohydride anion, BH4, has a nucleophilic B–H bond and can
donate those electrons into the π∗ orbital of a carbonyl compound
breaking that bond and eventually giving an alcohol as product.
 Having a region of high electron density
 Would give the carbon a negative one formal charge

Type of Electrophiles
5
The carbonyl group has a low-energy π* orbital ready to accept electrons
and also a partial positive charge on the carbon atom.
 Have a region of low electron density
 Would give the carbon a plus one formal charge

Reaction Mechanism and Active Species
6
Carbocation Carbon radical
Carbon Radical
Carbanion
Electron deficient species Electron rich species

Structural Effects on Reactivity
Orbital overlap controls angle of successful attack
7
 The energy levels of both nucleophile and electrophiles have same level or small
difference or have large difference
 So that for bond to form the electron has to jump to empty orbital of electrophile?

Addition Reaction
8
The chemistry of alkenes is generally subjected by addition reactions, most
of which occur through carbocation intermediates. The information covered
in the “Reaction Supplement” is vital to helping you understand the
reactions of alkenes. First we will cover the general mechanism of an
electrophilic addition reaction and then look at the regiospecificity of the
reaction and examine specific alkene addition reactions.

Addition Reaction
9
Addition reaction is defined as the reaction in which all the atoms of the
reagent are added to the reactant forming a single new product without
loss of any atoms.
The π-bond is broken Two new σ-bonds are formed
In an addition reaction, new groups X and Y are added to the starting
material. A π-bond is broken and two σ-bonds are formed.

 Electrophilic addition
 Nucleophilic addition
 Free radical addition
Types of Addition Reaction
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Addition to C=C double bond and C=Z bond (Z = heteroatom)
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 C=C double bond undergoes electrophilic addition
 C=Z double bond undergoes nucleophilic addition
 C=C-C=Z conjugated double bond undergoes nucleophilic
addition because C=Z bond is more stronger than C=C bond
and the addition takes place at C=C
Types of addition Reaction

13
The bonding in a molecule influences what will attack it
SINGLE
MULTIPLE
NON-POLAR
POLAR
A typical covalent bond with one shared pair –
nothing to tempt an attacking species
Bond has twice as many electrons – species
which like electrons will be attracted
Similar atoms have an equal attraction for the
shared pair of the covalent bond
Atoms have different electronegativities and the
shared pair will be attracted more to one end –
species known as nucleophiles will be attracted
to the slightly positive end
WHO IS ATTACKED?
d+ d-

14
Alkenes are much more reactive than alkanes
Alkenes contain a C=C bond
WHAT ATTACKS ALKENES?
C=C double bond is an electron rich area, thus can acts as nucleophile
Bonds are non-polar – no electron deficient areas
Therefore an electrophile can attacks alkene
ELECTROPHILIC ADDITION

Electrophilic Addition Reaction
Nucleophile:
- A “nucleus loving” species that donates an electron pair to an
electrophile
- Nucleophiles are also Lewis bases
- Alkenes (the π bond) also behave as nucleophiles
In this section, we will examine reactions in which an alkene
reacts with an electrophile to form a new compound. One of the
key factors we will consider is that of regioselectivity, which will
help us to determine on which alkene carbon the addition
reaction occurs.
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Electrophiles
 An “electron loving” species, which accepts an electron pair from a
nucleophile
 Electrophiles lack electron density and are in search of a negative
electron source
 Proton from acid, lewis acids such as BF3, AlX3, Br2, Metal ions that
contain vacant d orbitalsAg+, Hg++
Why do alkenes/alkynes undergo addition reaction ??
• Conversion of π bond to two s bonds is typically energy favorable
• 2e─ from the π bond form a new σ bond
• Two s bonds higher energy than one π + one s
• Overall process is thus typically exothermic
• π Electrons are exposed (above and below sp2 plane)
• π bonds are good at capturing electrophiles (H+, LewisAcids, X2)
• Metal Ions with vacant orbitals are also good electrophiles
Electrophilic addition to C-C double bond
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Electrophilic Addition
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 Before going through this section you needs to recall the chapter
structure and reactivity in terms of nucleophiles and electrophiles
 It is important to identify which reagent is electrophile and which one is
nucleophile
 This is an anti addition of halides to form a vicinal dibromide
Br2 has a low-energy empty orbital (the Br–Br s*), and is therefore acts as an electrophile
• The alkene’s filled π-orbital (the HOMO) acting as nucleophile will interact with the
bromine’s empty σ* orbital to give a product.
• A carbocation intermediate is formed
Electrophilic addition of bromine to ethylene

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Typical examples of Electrophilic addition reaction
Addition of Cl2/Br2 across C = C
If the electrophile forms a cyclic cation (bromonium ion) as an intermediate,
the nucleophile has no other option but to attack the intermediates from the
opposite side forming anti-adduct.
• Form vicinal dihalides as reaction products
• Non-nucleophilic solvent is used due to formation of reactive intermediate
• Important to run the reactions in dark to avoid radical formation

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 If the intermediate is a classical carbocation it may undergo rotation
about carbon-carbon σ-bond and the reaction will not be stereospecific.
 In some cases when the reagent is a dipole after the addition of the
electrophile the nucleophile may form intermediate ion-pair with the
carbocation and the addition will be syn.
 Reagents which form four membered cyclic intermediate (TS) also give
syn addition reaction. Examples: (1) addition of BH3, (2) addition of H2 in
presence of a catalyst.

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 Similar to what we saw in SN1 reaction: C+ has two faces
 T
op and bottom attack give two stereochemical products
 R and S enantiomers formed as a racemic mixture (50:50)
Stereochemistry in Addition Reaction

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 The bonding interaction of π-orbital (HOMO) interacts via end-on approach with
the σ* LUMO of Br2. In the mechanism the bromine polarized by the alkene
 A three-membered ring cyclic intermediate formed is called a bromonium ion.
Mechanism of electrophilic addition of bromine to alkene
 In the second step the bromonium ion acts as an electrophile, and it reacts with
the bromide ion lost from the bromine in the 1st addition step.
 Attack of Br– on the bromonium ion is a simple SN2 substitution i.e. from the side
opposite to the bridge
 Important: the orbitals involved are the HOMO of the bromide and the σ* of one
of the two C-Br bonds of the strained three-membered ring intermediate

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Formation of cyclic bromonium ion
Mechanism of electrophilic addition of bromine to ethylene
 Intermediate is a Bromonium ion (in Br2 Case)
 Nucleophilic solvents can Capture (Open) bromonium Ion
 Bromonium Ion Opening is SN2  AntiAddition of Br2
 The symmetric bromonium ion can be opened at either carbon
 Reaction products are enantiomers
 Racemic mixtures (50:50) in symmetric bromonium ions
 Will get excess of one enantiomer in asymmetric cases
 Stereospecific reactions: One stereoiomeric Form of the Starting Material
Reacts in Such a way to Form a Specific Stereoisomeric Form of the Product

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Formation of cyclic bromonium ion
 Intermediate is a Bromonium ion proven by the above reaction where a stable
bromonium ion was crystallized and characterized by x-ray crystallography.
 Backside attack by the bromide ion is not possible due to sterically hindered
adamentyl groups and improve the stability

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Why bromine should act as an electrophile as it is non-polar.
Explanation: as a bromine molecule approaches an alkene, electrons in the π-bond of
the alkene repel the electron pair in the Br-Br bond thus inducing a dipole.
As a non-polar bromine molecule
approaches an alkene, electrons in the
π orbital of the alkene repel the shared
pair of electrons in the Br-Br bond
The electron pair is now nearer one end so
the bromine molecule is polar and becomes
electrophilic.
Non-polar Polar

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Stereospecific reaction: Addition of bromine to cis- and trans-2-butene
 First step is formation of cyclic bromonium ion
 Second step is the attack of nucleophilic Br- to give overall anti-addition
 In “A” the bromonium ion has a mirror plane thus the two central carbons
are enantiotropic
 In “B” the intermediate bromonium ion has a C2 axis symmetry, thus the
two central carbons are homotropic
A
B

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Stereospecific reaction of bromine addition
 “open“ carbocation would give both cis and trans-products
 “cyclic” intermediate would give only trans-product, cis-product not
observed which is an indication of bromonium ion formation

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Addition of Br2 in 1-phenylpropene is regioselective
 The alkene has a phenyl group adjacent to the double bond, thus the selectivity
become less and both syn- and anti-products formed.
 The presence of phenyl group supports the carbocation formation by stabilizing
through resonance (benzyl carbocation)
 Thus reduce the strength of formation of bromonium ion and rotation along the
single bond occurs which gives both syn- and anti-addition products
 The syn-product predominates as the formation of ion pair is the key
intermediate
A free rotating open carbocation

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Addition of Br2/H2O in 1-propene gives halohydrin a regioselective product
 The regioselectivity explains on the basis of stability.
 The formation of secondary carbocation is more stable than the primary
carbocation.
 Thus, the highly substituted carbon atom has more electrophilic nature where
the nucleophilic H2O can preferentially attack.
 1-Bromo-2-hydroxypropane is formed as the major product than 2-bromo-1-
hydroxypropane
 In BrCN, C is sp hybridized and N is electron withdrawing, therefore Br
possesses partial +ve and CN retain partial –ve charge
Examples

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 In all these reactions the direction of arrow movement is very important
 Hydrogen added to the less substituted carbon according to the Markownikoff’s
rule and the more stable tertiary carbocation is formed
 Bromide ion in the second step reacts with the carbocation to form the product
Electrophilic addition of HBr to unsymetrical alkene
 Protonation of styrene gives a resonance stabilized benzylic carbocation

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Addition to unsymmetrical alkenes
Problem • addition of HBr to propene gives two isomeric brominated compounds
• HBr is unsymmetrical and can add in two ways
• products are not formed to the same extent
• the problem doesn't arise in ethene because it is symmetrical.
Mechanism
Two possibilities
Electrophilic addition to propene
Path A
Path B
According to Markownikoff’s rule in the addition to propene, path A involves a 2°
carbocation, path B a 1° carbocation.
As the 2° ion is more stable, the major product formed is 2-bromopropane (Path A)

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Energy profile of electrophilic addition of HX to propene
Energy diagram comparing addition of a HX to an alkene according to
Markovnikov’s rule (red) and the higher energy addition in the direction
opposite to Markovnikov’s rule (blue).

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Problem • addition of HCl to methoxyethene occurs as per Markownikoff’s rule
• The proton added to the 1° carbon
• The 2° carbocation formed will be stabilized by the electron donating
-OMe group
• the problem doesn't arise in ethene because it is symmetrical.
Mechanism
Electrophilic addition of HCl to Methoxyethene
The intermediate 2° carbocation stabilized by resonance with the methoxy group, thus
accelerate the reaction and control regioselectivity. +M effect dominant over -I effect of
OMe group
The major product formed is 1-bromo-1-methoxyethane
Resonance hybrid

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Problem • addition of aqueous HCl to methoxyethene occurs as per Markownikoff’s rule
• The proton added to the 1° carbon
• The 2° carbocation formed will be stabilized by the electron donating -OMe
group
• H2O acts as nucleophile to form hemi-acetal.
Mechanism
Electrophilic addition of aqueous HCl to Methoxyethene
The intermediate 2° carbocation stabilized by resonance with the methoxy group, thus
accelerate the reaction and control regioselectivity
The major product formed is 1-bromo-1-methoxyethane
Hydrolysis of hemi-acetal

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Problem • addition of HBr to 3,3,3-trifluoropropene occurs like anti-Markownikoff’s rule
• The proton added to the 2° carbon instead of terminal carbon
• The 2° carbocation if formed will be destabilized by the strong electron withdrawing
CF3 group, thus less stable than 1° carbocation
• The 1° carbocation is separated from CF3 group by two carbon atoms and therefore
destabilization by inductive effect is less
Mechanism
Electrophilic addition to 3,3,3-trifluoropropene
Markownikoff’s rule does not applicable to alkenes containing electron withdrawing group
Alkenes containing electron withdrawing groups

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Markownikoff’s rule
 When an unsymmetrical reagent adds to the double bond:
 the positive part (electrophile) of the reagent will attach to the carbon atom
containing more number of hydrogen atoms
 the negative part (nucleophile) of the reagent will join to the carbon atom
containing less number of hydrogen atoms
The reaction below can not prove the concept of Markownikoff’s rule as both carbon
has same number of hydrogen atoms. Therefore, it is important to understand the
reason behind the intermediate formation. In the electrophilic addition to alkenes the
major product is formed via the more stable carbocation (carbonium ion)
Modification of Markownikoff’s rule
Mixture product
Form via more stable carbocation

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Problem • addition of HBr to 2-methyl-1-phenylcyclohexene follow Markownikoff’s rule
• Benzylic carbocation is formed which is stabilize by resonance due to π-
delocalization
• Br- acts as nucleophile and attacks from the opposite site to the proton
following anti-addition to form regioselective product.
Mechanism
Electrophilic addition of HBr to unsymmetrical alkene
Propose the Mechanism

37
Problem • addition of HBr to 1-phenylpropene follow Markownikoff’s rule
• Benzylic carbocation is formed which is stabilize by resonance due to π-
delocalization
• Br- acts as nucleophile and attacks from the opposite site to the proton
following anti-addition to form regioselective product.
Mechanism
Electrophilic addition of aqueous HBr to unsymmetrical alkene
♦ The stabilization of carbocation intermediate by the phenyl group reduce the efficacy of
complex formation and an intimate ion pair may be formed as key intermediate
♦ The ion pair collapsed to the product before rotation about the single bond occur,
resulting in syn-addition as both proton and Br are on the same side.

38
Beyond electrophilic addition
Acid promoted isomerization of alkene
 First step is carbocation formation.
 The carbocations may trap a nucleophile or there is possibility that they may lose a
proton to give back an alkene.
 If the protonation is reversible, it is not necessary to be the same proton that is lost.
 A more stable alkene may be formed by losing a different proton, which means that
acid can catalyse the isomerization of alkenes — both between Z and E
geometrical isomers and between regioisomers.

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Regioselectivity in unsymmetrical bromonium ions
Addition to isobutene
The product is same whichever way the attack
takes place. Thus it is difficult to predict the
mechanism of bromination of unsymmetrical alkene
When a bromination is done in a nucleophilic solvent,
like water or methanol, the solvent molecules compete
with the bromide to open the bromonium ion.
• Two possible mechanism for attack of MeOH on bromonium ion. Either SN2 or SN1
• However, for SN2 there is a tertiary centre, thus, SN1 can be possible via open 3° carbocation (as in the right)
• The answer to the mystery is that substitution reactions don’t always go by pure SN1 or pure SN2 mechanisms,
but somewhere in between. The leaving group starts to leave, creating a partial positive charge on carbon which
is captured by the nucleophile (right figure)

40
Regioselectivity in unsymmetrical bromonium ions
Addition to isobutene
• The bromine begins to leave from bromonium ion, and a partial positive charge builds up
at the tertiary carbon than at the primary end. because the substituents stabilize the build-
up of positive charge at tert-carbon. One C–Br bond is longer and more polarized than the
other.
• The transition state has considerable positive charge on tert-carbon, and is known as a
loose SN2 transition state.
 The reaction of Br2/H2O with isobutene forms bromohydrin.
 When treated with base, a rapid intramolecular SN2 reaction follows: bromide is expelled
as a leaving group and an epoxide is formed. An useful alternative synthesis of epoxides
avoiding peroxy-acids.

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Rearrangement in electrophilic addition reaction
 The initially formed carbocation may not react with the nucleophile
 The initially formed carbocation can however undergoes molecular rearrangement to form a
more stable carbocation which is stabilized by hyperconjugation or resonance
Addition of HBr with unsymmetrical alkene

42
Stereochemistry of electrophilic addition reaction
 There are three key categories of alkene reaction pathways:
 An non-stereoslective mixture of syn vs anti addition product - e.g. addition of HX to alkene
 Reactions that are stereoslective for the syn addition product - e.g. addition of Pd-C/H2 to
alkene
 Reactions that are stereoslective for the anti addition product - e.g. addition of Br2 to alkene

As the alkynes are unsaturated we might expect that they will undergo
addition reactions like the alkenes. This is indeed the case but the
reaction can happen in two stages and, with care, can be stopped after
the first stage.
Halogenation – to make dihaloalkenes, then tetrahaloalkanes
Electrophilic Addition of Alkynes

Hydrogenation – to make alkenes and then alkanes
Reaction with HX – to make haloalkenes and then dihaloalkanes
Electrophilic Addition of Alkynes
This addition of hydrogen across a double bond happens only in the presence of a metal
catalyst, usually platinum. Hydrogenation occurs on the surface of metal.

45
Thermodynamic versus Kinetic Control Reactions
 The thermodynamic product is the most stable product
 The thermodynamic product predominates when the reaction is reversible (thermodynamic control)
 The kinetic product is the product that is formed most rapidly
 The kinetic product predominates when the reaction is irreversible (kinetic control)
Formed faster More stable
Electrophilic addition to conjugated dienes

Reaction of 2-methylbutadiene with HBr is a kinetically controlled reaction?
46
one resonance form is tertiary
carbocation; other is primary
one resonance form is secondary
carbocation; other is primary
 The reaction follow SN1 mechanism as it form a stable carbocation which is both
tertiary and allylic.
 The unsymmetrical carbocation is attacked by Br- only at the less substituted
primary carbon atom to form prenyl bromide as major product
Major product
Structural Effects on Reactivity
 x


Addition of HBr to 4-methylpenta-1,3-diene
1,4-addition product is not always the thermodynamic product
47
Reason: 1,2-addition product is both kinetically and thermodynamically stable as in the
intermediate alkene is most stable and the carbocation is secondary.
kinetic product
thermodynamic product
Addition of HBr to 2-methylpenta-1,3-diene
1,4-addition product is not always the thermodynamic product
Reason: The alkene is stable one and the carbocation is tertiary.
kinetic product
thermodynamic product
Attack is not possible
due to steric crowding

Reaction of 2,4-hexadiene with HBr
48
The carbocation formed is a secondary one.
So kinetic product predominate.
Both products have the same stability.
Reaction of 2,5-dimethylhexa-2,4-diene with HBr
2o carbocation 3o carbocation
• Proton adds to end of the diene forming
an allylic carbocation
• Both alkenes are stable but the allylic
rearrangement gives more stable
tertiary carbocation
• Thus, the 1,4-adduct is major product

Addition of Br2 to butadiene
49
 If the reaction is done at lower temperatures, the bromine just adds across one of the
double bonds forming a 1,2-dibromide.
• At higher temperature 1,4-product dominates as it is more stable than 1,2-adduct and it
has a more substituted double bond and the two large bromine atoms are further apart.
Thermodynamic
Kinetic product

Hydroxylation
50
Alkene hydroxylation does not involve a carbocation intermediate but rather is thought to occur
through an intermediate cyclic osmate formed by the addition of OsO4 to the alkene. The cyclic
osmate is then cleaved (broken) in a separate step using aqueous sodium bisulfate, NaHSO3.
A reaction in which the -OH group is added to both alkene carbons forming a diol
The product is called a diol (short for “di – alcohol”), which is also known as a glycol. The
reaction does not occur via the traditional electrophilic addition mechanism because no
carbocation is formed.

Epoxidation: Oxidation of alkene with peracids
(CH3COOOH, HCOOOH, C6H5COOOH, m-Cl-C6H4COOOH)
51
The rate of epoxidation increased in the presence of
 electron withdrawing groups in the peroxy acid
 electron donating groups in the alkene
 The oxidation proceed via a concerted process (proceed without any carbocation
intermediate). The two bonds to the alkene forms at the same time and therefore does not
change the stereochemical relationship.
 The peroxyacid acts as electrophile. The reaction is stereospecific and formed by syn-
addition to the double bond
 Terminal alkene reacts slowly compared to alkyl-substituted alkenes, i.e. the rate of
epoxidation is increased by increasing alkyl groups and the presence of e--donating groups.
 The attack preferred from the less hindered side of the double bond
A process of addition of oxygen to convert alkene to three membered epoxide ring in the
presence of peracid

Epoxidation: Oxidation of alkene with peracids
(CH3COOOH, HCOOOH, C6H5COOOH, m-Cl-C6H4COOOH)
52
Reaction is stereospecific and formed by syn-addition to the double bond
For conformationally rigid cyclic alkene the reagent approach from the less hindered
side of the double bond
Examples
Terminal alkene reacts slowly compared to alkyl-substituted alkenes
Retention of
stereochemistry
Preference over conjugated alkene
More substituted alkene

Epoxide ring opening is stereospecific
53
Acid catalysed hydrolysis gives anti-
hydroxylation, follow SN2 mechanism
to give inversion product
Follow syn-addition to the alkene and
gives cis-diol after hydrolysis. The
reaction is stereospecific
Mechanism
The mechanism proceed via SN2
mechanism giving inversion product
as teh two groups end up trans across
the ring forming trans-diastereomer
product.
(±)

Epoxide ring opening is stereospecific
54
• In base-catalysed cleavage by methoxy group follow SN2 mechanism to break one of the C-
O epoxide under basic or neutral conditions. The nucleophile attack to the less sterically
hindered carbon giving inversion product
• In acid-catalysed cleavage by methanol follow SN1-type mechanism. The epoxide on
protonation form a weak C-O bond which interact with the nucleophile in the transition
state.
• The highly substituted carbon stabilize the developing +ve charge, so the nucleophile can
attack. The nucleophile attack preferentially to the more substituted carbon. Here the
formation of tert-carbocation is more stable than the other which could form sec-
carbocation. The reaction is regioselective.

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• Isobutene on treatment with bromine/water form bromohydrin,
which when treated with a base deprotonate the alcohol.
• Than a rapid intramolecular SN2 reaction follows: bromide is
expelled as a leaving group and an epoxide is formed.
Epoxidation without peracid
• Stabilize the peroxy acid by H-bonding in
the transition state, thus attack to the side
of the C=C close to the OH group. Cis-
epoxide is the major product
• No H-bonding possible, thus attack
occurs from less hindered side of the
C=C double bond. Trans-epoxide is the
major product.
Comparison between the role of alcohol and acetate on epoxidation:
Epoxides can be formed from
compounds containing an adjacent
hydroxyl group and a leaving group
by treatment with base.

56
• It is an enantioselective reaction and useful for epoxidation of allylic
alcohol using catalyst titanium tetraisopropoxide,
Ti[OCH(CH3)2]4 and one enantiomer of diethyl tartrate (DET):
• Converts primary and secondary allylic alcohols into 2,3-epoxyalcohols
• The reaction is enantioselective (only one enantiomer produced)
• Enantiomer formed depends on stereochemistry of catalyst
Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 18, 5974-5976
Sharpless assymetric epoxidation

57
• The catalyst istitanium tetra(isopropoxide) with diethyltartrate.
• The use of + or –tartrate will yield different enantiomers
• tert-Butylperoxide is used as the oxidizing agent
• Dichloromethane solvent and -20 ºC temperature

58
First, the oxidizing agent (t-BuOOH) is added to the
mixture, it displaces one of the remaining isopropoxide
ligands and one of the tartrate carbonyl groups. For this
oxidizing complex to react with an allylic alcohol, the
alcohol must become coordinated to the titanium too,
displacing a further isopropoxide ligand. Because of the
shape of the complex the reactive oxygen atom of the
bound hydroperoxide has to be delivered to the lower face
of the alkene, and the epoxide is formed in high
enantiomeric excess.
Mechanism

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Reaction of epoxides
Formation of trans-1,2-diol
For synthesis of allyl alcohol
Reaction with Grignard reagent
Rearrangement of epoxide ring
Rearrangement of epoxide ring

Indirect Hydration
60
 Oxymercuration-Demercuration
 Markovnikov product formed
 Anti addition of H-OH
 No rearrangements
 Hydroboration
 Anti-Markovnikov product formed
 Syn addition of H-OH

Addition involving metal ions (Mercuration - Reduction)
61
 Transition metal (Hg) used in the dehydration of alkene
 Hg(II) cation as soft electrophile interact with the soft nucleophile alkene
 First complex formation between alkene and Hg(II) to form a cyclic mercurinium ion
intermediate, a three-membered ring with a positive charge.
 Majority of the +ve charge located on Hg and a fraction on the more substituted carbon. This
is sufficient for Markownikoff’s orientation but not enough for carbocation rearrangement.
 Water attach at the more substituted end of +vely charged mercurinium ion
 NaBH4 a reducing agent, is used to reduce the weak C-Hg bond and replaces the mercury
with hydrogen.
Proceed via carbocation rearrangement
Example

Oxymercuration is stereospecific
62

63
Hydroboration: The reaction is regioselective
 Borane, BH3, adds a hydrogen to the most substituted carbon in the double bond.
 The alkylborane is then oxidized to the alcohol give anti-Markownikoff product.
 Borane exists as a dimer, B2H6, in equilibrium with its monomer.
 Borane is a toxic, flammable, explosive gas. Safe when complexed with tetrahydrofuran.

64
Hydroboration: The reaction is regioselective
• Hydroboration is a syn-addition across the alkene.
• First coordination of empty p-obital of boron with the π-electron of alkene
• Boron is less electronegative than hydrogen and so the regioselectivity is normal. Boron atom attached
to the less substituted and less sterically hindered carbon.
• The C–B bond goes ahead of formation of the C–H bond so that boron and carbon are partially charged
in the four-centred transition state. Thus, both new C-B and C-H bonds are formed from the same side
• The alkyl boron formed is not stable and reacts with alkaline H2O2 to give the corresponding alcohol

65
Reaction carbenes with alkenes
• The mechanism of this type of reaction depends on whether the carbene is a singlet or a triplet.
• Singlet carbenes, like this one here (remember that electron-rich substituents stabilize the singlet
spin state), can add to alkenes in an entirely concerted manner shown above.
• The reaction is stereospecific.
Cyclopropanation of alkene: Insertion of -CH2 group into a double bond producing a cyclopropane ring.
• Carbene basically acts as electrophile
as the carbon atom has only six
electrons
• Carbene has Some nucleophilicity due
to the presence of lone pair.
Generation of carbene

66
Reaction carbenes with alkenes cyclopropanes
• The alkene insertion reaction is stereospecific only for singlet carbenes.
• For triplet carbenes, the reaction is non-stereospecific.
• Although carbenes formed thermally from diazoalkenes initially be singlets, they can be transformed
to more stable triplet carbene by acquiring energy photochemically.
• The addition of triplet carbene to the alkene is a radical reaction
• The diradical intermediate also lives long enough for C–C bond rotation and loss of stereochemistry.
• Because the electrons in triplet carbene are not paired the second bond can only form once one of
the two electrons has flipped its spin.

67
• The diradical intermediate also lives long
enough for C–C bond rotation and loss of
stereochemistry.
• Because the electrons in triplet carbene are not
paired the second bond can only form once one
of the two electrons has flipped its spin.

68
• Inert solvent such as C3F8 (perfluoropropane) then :CH2 undergoes more collisions before it reacts
and so the chances of spin-flipping of singlet :CH2 to triplet :CH2 is increased.
• The reaction is stereospecific for singlet carbene and stereoselective for triplet carbene
Addition of singlet carbenes is a [1+2] cycloaddition Addition of triplet carbenes is a radical reaction
• Carbene substituted with electron-withdrawing carbonyl groups, are even more powerful
electrophiles than carbenes like :CCl2, and will even add to the double bonds of benzene.
• The product is not stable, and immediately undergoes electrocyclic ring opening.

69
• According to the orbital symmetry we might say the empty p orbital of the carbene (LUMO)
interacting with the π-bond (HOMO) of the alkene or the lone pair of the carbene in its filled sp2
orbital (HOMO) interacting with the π* antibonding orbital of the alkene (LUMO).
• However in both way there is a antibonding interaction.
• However, two new bonds can be formed if the carbene approaches the alkene in a ‘sideways-on’
manner.

70
Simmons–Smith reaction
The reaction of alkene to the zinc carbenoid formed by the reaction of diiodomethane with zinc metal
to produce a cyclopropane. Zinc carbenoid reacts like a carbene
• The reaction is like transfer of a carbene from the metal to the alkene without formation of any
free carbene.
• When an allylic alcohol is cyclopropanated, the new methylene group adds stereoselectively to
the same face of the double bond as the alcohol group
• Allylic alcohols also cyclopropanate over 100 times faster than their unfunctionalized alkene
equivalents. Coordination between the zinc atom and the hydroxyl group in the transition state
explains both the stereoselectivity and the rate increase.
Mechanism

71
Addition to cyclopropane ring
• The reaction usually follow Markownikoff’s rule
• The electrophile attach to carbon with the most hydrogen and
nucleophile goes to the carbon that can be more stabilize the
+ve charge
• In presence of UV light the reaction with Br2, Cl2 follow radical
mechanism
• Addition of cyclopropane involves electrophillic addition.
Substituted cyclopropane follow markonikov’s rule.
Cyclopropane ring in some cases resembles C=C double bond. Therefore, addition reaction is possible
Addition of HBr to a C-C σ-bond of a cyclopropane ring results in new C-H and C-Br bonds where
the cyclopropane C-C bond was ruptured
The large ring strain :
bent Banana bond
Conjugative addition

72
Ozonolysis of alkenes
• Reaction with ozone forms an ozonide.
• Ozonides are not isolated, but are treated with a
mild reducing agent like Zn or dimethyl sulfide.
• Milder oxidation than permanganate.
• Products formed are ketones or aldehydes.
ozonide—is the first stable product of
the reaction with ozone.
The cycloaddition product is highly
unstable. The O–O single bond (bond
energy 140 kJ mol–1). Decompose by
a reverse 1,3-dipolar cycloaddition.

73
Ozonolysis of alkene
Some reaction…

75
 Alkenes itself behaves as nucleophiles and can not react with nucleophiles
 Addition of nucleophiles to C=C would result the formation of an unstabilized
anion, the conjugate base of an alkane.
 Alkanes are extraordinarily weak acids.
 However, any favourable structural changes on C-C double bond will make the
nucleophilic addition reaction possible.
 If a electron withdrawing substituent is present on double bonded carbon it will
decrease the electron density on carbon hence nucleophilic addition will be
facilitated.
Michael addition
Nucleophilic Addition

Epoxidation: Oxidation of α,β-unsaturated alkene with peracids
76
α,β-Unsaturated alkene epoxidized by alkaline hydrogen peroxide
o Hydroperoxide is a good nucleophile because of the alpha effect: interaction of the two
lone pairs on adjacent oxygen atoms raises the HOMO of the anion and makes it a
better and softer nucleophile than hydroxide.
o Hydroperoxide is also less basic than hydroxide because of the inductive electron-
withdrawing effect of the second oxygen atom.
o Hydroperoxide anion can form by treating H2O2 with aqueous OH-
o hydroxide is lost from enolates in E1cB eliminations, and here the bond breaking is a
weak O–O bond. The product is an epoxide.

Epoxidation: Oxidation of α,β-unsaturated alkene with peracids
77
 The electrophilic epoxidizing agents such as m-CPBA, is less effective with electron-deficient alkenes and
a nucleophilic epoxidizing agent is necessary. m-CPBA epoxidation is stereospecific because the reaction
happens in one step.
 However. nucleophilic epoxidation is a two-step reaction: there is free rotation about the bond marked
in the anionic intermediate, and the more stable, trans-epoxide results, whatever the geometry of the
starting alkene.
Mechanism:

Addition of HCN to α,β-unsaturated carbonyl (C=C-C=O) compounds (but-3-en-2-one)
78
 Conjugate addition to the C=C double bond
follows a similar course to direct addition to the
C=O group
 Both mechanisms have two steps: addition,
followed by protonation.
 Conjugate additions only occur to C=C double
bonds next to C=O groups.
 Addition do not occur at C=C bonds that aren’t
conjugated to C=O
Thermodynamic product
more stable
Kinetic product
forms faster

Addition of HCN to to alkyne
79
Addition of alcohols

Conjugate Addition
80
• When the EWG is a carbonyl group, there can be competition with 1,2-addition, which is
generally for aldehydes but can also occur with ketones.
• With successively less reactive carbonyl groups, 1,4-addition becomes more favorable.
• Highly reactive, hard nucleophiles tend to favor 1,2-addition and the reaction is irreversible if
the nucleophile is a poor leaving group. For example with organometallic reagents, 1,2-
addition is usually observed and it is irreversible because there is no tendency to expel an
alkyl anion.
• With less basic nucleophiles, the 1,2-addition is more easily reversible and the 1,4-addition
product is usually more stable.

Michael Addition
81
 A reaction between enolate forming component and an active alkene conjugated to any
group with –M effect, such as -COOR, -CN, -NO2, etc.
It is the nucleophilic addition of carbanion or a nucleophile to an α,β-unsaturated carbonyl compound

Michael Addition
82
It is the nucleophilic addition of carbanion or a nucleophile to an α,β-unsaturated carbonyl compound
Robinson annulation reaction: Formation of alicyclic rings
The first step, Michael addition, creates a stereogenic centre but no relative stereochemistry.
In the second step - the aldol cyclization - that the stereochemistry of the ring junction is decided.

Intramolecular acylation: Dieckmann reaction
83
• Intramolecular acylations often used to form five- or a six-membered ring.
• A classic case is the cyclization of the diethyl ester of adipic acid (diethyl hexanedioate), a
component in nylon manufacture.
• The ethyl acrylate, a cancer suspecting agent, attack enzymes,particularly the vital DNA
polymerase involved in cell division by conjugate addition to thiol and amino groups in
the enzyme.

Examples: Predict the mechanism of the following conjugate addition reactions.
84
1)
2)
3)
4)
6)
7)
8)
9)
5) 10)
11)

85
Keto−Enol Tautomerism
Acidity of α-H (pKa):
Intramolecular
hydrogen bonding

86
 Protonation of carbonyl group by an acid catalyst HA yields a cation that can be
represented by two resonance structures
 Loss of H+ from the α-position by reaction with a base A- then yields the enol
tautomer and regenerates the HA catalyst
Acid catalyzed enol formation

87
 Base removes an acidic proton from the α-position of the carbonyl compound,
forming an enolate anion that has two resonance structures
 Protonation of the enolate anion on the oxygen atom by water yields an enol and
regenerates the base catalyst.
Base catalyzed enol formation

88
Bidentate Property of Enolate Ion

89
Reduction with LiAlH4
• LiAlH4 is one of the most powerful reductants. A strong hydride donor reagent
• highly flammable reagent and therefore must be used with care
• reactions are normally carried out in ethereal solvents (e.g. THF, Et2O); LiAlH4 reacts
violently with protic solvents (c.f. NaBH4)
• The extremely high reactivity of LiAlH4 imparts relatively low levels of chemoselectivity
on this reagent. However it is most reactive towards strong electrophiles.

90
• LiAlH4 is a stronger hydride donor reagent compared to NaBH4
Due to bulky methyl group at C3-
position, equatorial attack prefer thus
the formation axial alcohol.
Axial attack prefer due to no steric
hindrance

91
• Reduction of ester, amide, nitrile, azide, epoxide
Oxygen is a better leaving group than nitrogen
Propose the mechanism of the following reactions?

Addition to C=O bond
92
The addition is a nucleophilic reaction. The nucleophile attacks to the partially electropositive C atom
forming a tetrahedral intermediate which on treatment with acid gives the corresponding alcohol
Addition of Grignard reagent
RMgX
H2O
HCN
NH2NH2
 Grignard reagents are prepared from the reaction of alkyl halides with magnesium
in dry ether as the solvent.
 The alkyl group assumes a negative character and served as a nucleophile.
 When added to an aldehyde or ketone, the Grignard reagent attacks the carbonyl
carbon in a base-initiated nucleophilic addition.
 Neutralization of the negative intermediate in acidic medium results in the
preparation of an alcohol.

93
Preparation of Grignard reagent
 Metalation of hydrocarbon using prepared Grignard reagent: The formation of a
more stable carbanion
 Metals are highly electropositive, therefore, metal containing reagents are strong
source of nucleophilic carbon
 Highly polar
 Very strong Lewis base
 Strongly polarized C-M bond

94
Addition of Grignard reagent
 In the case substituent which can acts leaving group, the initially formed adduct can
convert back to C=O bond which then react further with a second reagent to give an
alcohol
Examples

Aldol Condensation
95
Reaction of two C=O compounds in presence of the base: Base catalysed
Acid catalysed Aldol condensation:
Occurs with compounds
containing α-hydrogen atom

Aldol Condensation
96
Examples of Intramolecular Aldol reaction: Practice the mechanism of the following reactions

97
Reformatsky Reaction
• A cross condensation reaction leading to aldol type products
• Reaction involves addition of organozinc reagent to the carbonyl group of an aldehyde or
ketone to generate β-hydroxyl ester by extension of carbon skeleton.
• Organo Zn is less reactive compared to Grignard reagent and can not react with ester
Probable binding of Zn for
favourable reaction with
aldehyde/ketone

Mannich Reaction
98
The reaction involves an amine and aldehyde which form an iminium ion intermediate. The iminium
ion then reacts with a compound containing active hydrogen atom
Mannich base is the product of the Mannich reaction
Eschenmoser salt
(Electrophile in character)

Mannich Reaction
99
Reaction of acetophenone with diethylamine and formaldehyde gives the Mannich base which on
Hoffmann elimination using a base produces 1-phenyl-2-propenone
Examples: Suggest the mechanism of the following reactions
Why in indole the reaction of
iminium ion reacts at the 3-position
instead of 2-position

100
The aldol condensation thus far has been limited to reactions in which simple carbonyl compounds
are involved. However, most stabilized anions can act as nucleophiles with carbonyl molecules to
lead to aldol and α,β-unsaturated product.
The condensation of aldehyde and ketones, usually not containing an α-hydrogen with compounds
having an active methylene group, e.g. malonic ester, cyanoacetic acid, malononitrile can takes place
even with a weaker base to produce the condensation product.
The base is used to create an anion. This anion is then react with an aldehyde
Some examples of compounds
with active methylene group
Knoevenagel Condensation
Example
Device a reaction mechanism
for the following condensation
products

101
Reaction of aromatic aldehyde with anhydride of aliphatic acid catalysed by sodium/potassium
salt of that acid
The reaction used for the synthesis of α,β-unsaturated acids and is an aldol type condensation
Perkin Condensation
Mechanism

102
Reaction of cyanide ion mediated intermolecular condensation of two molecules of aromatic
aldehyde to give an α-hydroxyketone (acyloin).
A strong base can deprotonate at the carbonyl carbon to give a carbanion which reacts with a
second molecule of benzaldehyde. The cyanide catalyst is regenerated for further the reaction.
The cyanide ion acts as a strong nucleophile and has the ability to delocalize the –ve charge on
the carbanion.
Benzoin Condensation

103
The reaction between a carbonyl compound and a species known as phosphonium ylides to
give alkene as the major product. The reaction also called as Wittig olefination reaction.
Wittig Reaction
Preparation of phosphonium ylide
• An ylide is a species with +ve and –ve charges on adjacent atoms
• It is prepare in two steps:
– First, the reaction of PPh3 with an alkyl halide by SN2 reaction gives a
phosphonium salt (nucleophilic displacement of halide by PPh3.
– Second, removal of the acidic proton (pKa = 35) on the carbon atom near the
phosphonium by a strong base like butyllithium, NaH, NaNH2.
• The phosphorous atom carries the +ve charge and the carbon carries the –ve charge

104
Wittig Reaction
The reactivity of phosphorous ylide strongly depends on substituents
• When electron withdrawing group is present the reactivity at the ylide carbon reduced
• R can be alkyl or aryl
• Ylides are sensitive towards water and oxygen
• Mostly the unstabilized ylides are highly reactive thus performed under inert condition
The –vely polarized carbon centre (nucleophile) attacks to the C=O carbon which is the rate
determining step.

105
Wittig Reaction
• Non-stabilized ylides require a strong base like BuLi, NaH under inert condition
• When –M group such as C=O group attached to the ylide carbon stabilized the –ve charge by
resonance
• Thus, the phosphorane can be prepared by treatment of phosphonium ion with less strong
base e.g. sodium alkoxide, hydroxide and carbonate
• A resonance stabilized ylide allows the formation of more stable E isomer
• While with unstabilized ylides the reaction is Z selective, e.g. alkyl group
Stereochemistry
• It is non-stereospecific: Both E- and Z-alkene are formed E- and Z-alkene
• Oxaphosphetane undergo stereospecfic syn-elimination to give the corresponding E- and Z-
alkene

106
Wittig Reaction
Reactions

107
Baeyer-Villiger oxidation
• Ketone on treatment peracids in the presence of acid catalyst give an ester by insertion of
oxygen next to the carbonyl group.
• The mechanism of this reaction involves a nucleophilic attack of the peracid on the carbonyl
carbon gives an intermediate which rearrange with the loss of an anion of an acid.
• In an unsymmetrical ketone the group which is more nucleophilic will migrate due to its ability
to supply electrons (electron donor).
• The order of migration is: tertiary > secondary > primary > Me
• Migration of aryl group preferred over Me-group, follow intramolecular concerted mechanism

108
Baeyer-Villiger oxidation
• Suggest the product from the following reactions with mechanism.

Free Radical Addition
110
Addition of HBr to alkene: (anti-Markovnikov)
• Free radical – A species with an unpaired electron
• In the presence of peroxides, HBr adds to an alkene to form the “anti-
Markovnikov” product.
• Peroxides produce free radicals.
• Only HBr has the right bond energy to form addition product with alkene.
• HCl and HI do not undergoes free-radical addition to alkene in the presence of
peroxide because:
– The HCl bond is too strong, and abstraction of H from HCl is endothermic.
So it will add according to Markovnikov’s rule, even in the presence of
peroxide.
– Addition of I• to C=C double bond is endothermic. The HI bond tends to
break heterolytically to form ions, it will also add according to
Markovnikov’s rule.

111
Addition of HBr to alkene: (anti-Markovnikov)
• Addition of HBr to alkene occurs in the presence of peroxide initiator
• The active alkoxy radical formed by homolytic cleavage of O-O
Mechanism
Initiation (homolytic cleavage)
Propagation
 The alkoxy radical abstract the proton from HBr forming Br radical
 The Br radical then reacts with the alkene to form a cabon radical which then abstract a H
atom from HBr to form adition product.
 The regenerated Br radical then react with another alkene molecule and continue the
chain reaction.

112
Termination
• The reaction can be terminated by self reaction of Br radical or addition to carbon radical
J. Am. Chem. Soc., 1952, 74, 3588-3592
J. Org. Chem., 1969, 34, 3112
Regioselective
Stereoselective J. Am. Chem. Soc., 1958, 80, 5997
Problems

References
• Advanced Organic Chemistry: Reaction Mechanism and Structure (Wiley
Eastern Limited), by Jerry March
• Organic Chemistry (Second Edition), by J. Clayden, N. Greeves, S.
Warren
• A Guidebook to Mechanism in Organic Chemistry by Peter Sykes
• Organic Reactions and their Mechanisms, New Age Science, by P. S.
Kalsi
• Organic Reaction Mechanisms (Fourth Edition), Narosa Publishing
House, by V.K. Ahluwalia & R. K. Parashar
• Mechanism and theory in organic chemistry, Harper & Row, by T. H.
Lowry, K. S. Richardson
• Advanced Organic Chemistry: Part A: Structure and Mechanisms,
Springer Science & Business Media, F. A. Carey, R. J. Sundberg
• Organic Chemistry by Robert T. Morrison and Robert N. Boyd
113

Problems
114
 The first step is a simple addition of cyanide to a ketone usually carried out with
NaCN and acetic acid.
 The second step is an acid-catalysed addition of an alcohol to a nitrile.
 Finally there is a double addition of an organometallic reagent to an ester.

115
This stable product can be isolated from the reaction between benzaldehyde
and ammonia. Suggest a mechanism.
Imine formation follows the usual pathway but this imine is unstable, as are most
primary imines, and it reacts with more benzaldehyde. This reaction starts normally
enough but dehydration of the first intermediate produces a strange looking cation with
two double bonds to the same nitrogen atom. Addition of another imine gives the final
product. The benzene rings play no part in these reactions so we shall represent them
as Ph, but they do stabilize the final product by conjugation with the imines.
Problems

116
Predict the orientation of HCl addition to these alkenes.
The first and last alkenes have different numbers of substituents at each end of the
alkene and will give the more stable, more highly substituted cation on protonation.
The middle one has the same number of substituents (one) at each end but they are
very different in kind. The secondary benzylic cation is preferred to the non-conjugated
alternative.
Problems

117
Suggest mechanism and products for these reactions.
The mechanism is bromonium ion formation by electrophilic attack of bromine on the alkene and
trans opening of the bromonium ion by bromide ion. Same mechanism for both reactions.
What will be the products of the addition of bromine water to these alkenes?
The bromonium ion is formed again but now water attacks as the nucleophile as it is in large excess
as the solvent. If the alkene is unsymmetrical, water attacks the more substituted end of the
bromonium ion with inversion of configuration.
Problems

118
By working at low temperature with one equivalent of buffered solution of a peroxy-acid, it is possible to
prepare the monoepoxide of cyclopentadiene. Why are these precautions necessary and why does a
second epoxidation not occur under these conditions?
The other questions concern the low temperature, which favours the kinetic product and encourages
epoxide formation on the remaining alkene. A by-product from the reaction is RCO2H which could
catalyse the opening of the epoxide to give a stable allyl cation (p. 336 in the textbook). The buffer
prevents the mixture becoming too acidic.
In this electrophilic addition the stability and selectivity needs to be considered.
One of the alkenes in the diene reacts in the usual way to give, first of all, the monoepoxide. The
reaction can be stopped there only if the remaining alkene is less nucleophilic than the alkenes in
cyclopentadiene. This is indeed the case because the HOMO of a diene is higher in energy than the
HOMO of a simple alkene. The HOMO of the diene (Ψ2) results from antibonding addition of the two
separate π-orbitals, making the diene more reactive than an isolated alkene.
Problems

119
Explain the formation of the product.
Addition of bromine occurs first to give the trans dibromide. Base then eliminates one of the
bromides in an E2 reaction using the only available trans hydrogen atom. This gives a reactive allylic
bromide that reacts with cyanide ion by a favourable SN2 reaction to give the product.
An electrophilic addition followed by an elimination and a substitution
Suggest mechanisms for the following reactions.
Problems

Msc Organic reaction mechanism and reaction

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