Mecanisme de Reactie

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ADVANCED ORGANIC CHEMISTRY -I (MPC 102T) UNIT-I: Basic Aspects of

Organic Chemistry Types of Reaction Mechanisms and Methods of
Determining Them
Presentation · August 2019

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ADVANCED ORGANIC CHEMISTRY – I (MPC 102T) UNIT- I: Basic Aspects of Organic Chemistry
Types of Reaction Mechanisms and Methods of Determining Them
- Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types
are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions,
photochemical reactions and redox reactions. In organic synthesis, organic reactions are used in the construction of
new organic molecules.
REACTION TYPE SUBTYPE COMMENT
 Electrophilic Addition
Include such reactions as halogenation, hydrohalogenation
Addition Reactions  Nucleophilic Addition
and hydration.
 Radical Addition
Include processes such as dehydration and are found to
Elimination Reaction
follow an E1, E2 or E1cB reaction mechanism
 Nucleophilic Aliphatic
With SN1, SN2 and SNi reaction mechanisms
Substitution
 Nucleophilic Aromatic
Substitution
 Nucleophilic Acyl
Substitution Reactions Substitution
 Electrophilic
Substitution
 Electrophilic Aromatic
Substitution
 Radical Substitution
 1,2-Rearrangements
Rearrangement Reactions  Pericyclic Reactions
 Metathesis
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University Page | 1
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
 ADDITION REACTIONS
- Addition Reactions reaction are those in which atoms or groups of atoms are simply added to a double bond
without the elimination of atoms or other molecules.
Addition of chlorine to ethylene
- In this reaction at least one pie (π) bond is lost while two new sigma (σ) bonds are formed.
- Double bonds become saturated, triple bonds are converted into double bonds or many become saturated by further
addition.
- Addition reactions possible to the chemical compounds that have multiple bonds, such as molecules with carbon–
carbon double bonds (alkenes), or with triple bonds (alkynes). Molecules containing carbon-hetero double bonds
like carbonyl (C=O) groups, or imine (C=N) groups, can undergo addition, as they too have double bond character.
- An addition reaction is the reverse of an elimination reaction. For instance, the hydration of an alkene to an alcohol
is reversed by dehydration.
- There are two main types of polar addition reactions: (i) electrophilic addition and (ii) nucleophilic addition.
Two nonpolar addition reactions exist as well, called (i) free radical addition and (ii) cycloadditions. Addition
reactions are also encountered in polymerizations and called addition polymerization.
Electrophilic addition to alkene
Nucleophilic addition of nucleophile to carbonyl
Free radical addition of halide to alkene
A concerted combination of two π-electron systems to form a ring of atoms having two
new σ bonds and two fewer π bonds is called a cycloaddition reaction.
 ELIMINATION REACTION
- Elimination Reaction are those which involve the removal of atom or group of atom from two adjacent in the
substrate molecules to form a multiple bond.
- Elimination Reaction may be regarded as reverse of addition reactions.
- In this reaction two sigma (σ) bonds are lost and a new pie (π) bond is formed.
- Saturated compound become unsaturated.
- An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in
either a one or two-step mechanism. The one-step mechanism is known as the E2 reaction, and the two-step
mechanism is known as the E1 reaction.
- In most organic elimination reactions, at least one hydrogen is lost to form the double bond: the unsaturation of the
molecule increases. It is also possible that a molecule undergoes reductive elimination, by which the valence of an
atom in the molecule decreases by two, though this is more common in inorganic chemistry. An important class of
elimination reactions is those involving alkyl halides, with good leaving groups, reacting with a Lewis base to form
an alkene.
Elimination reaction of cyclohexanol to cyclohexene with sulfuric acid and heat
 SUBSTITUTION REACTIONS
- Substitution Reactions are those reaction in which atoms or groups of atoms are directly attached to a carbon in the
substrate molecule is replaced by another atom or group of atoms.
- Substitution reaction also known as single displacement reaction or single substitution reaction.
- Substitution reactions in organic chemistry are classified either as electrophilic, free radical or nucleophilic
depending upon the reagent involved.
- Substitution versus Elimination: Substitution and elimination reactions often compete with each other because due
to it’s nucleophilic or basic properties.
- Substitution and elimination reactions are strongly influenced by:

1. Increasing the temperature tends to increase elimination due to disorder / entropy effects
2. Increasing steric effects (look at both "R" and the "Nu/B") tends to increase elimination.
3. The basicity / nucleophilicity of the attacking species i.e. switching from ROH to RO- will increase the
amount of elimination
Leaving
Reaction Substrate Nu or Base Solvent Examples
Group (LG)
Strong Weak alkyl halide /AgNO3/ aq. EtOH
Strong Very Strong
SN 1 (3o or resonance (Good Nu and alcohol / HX (note X is a good
(Good LG) (Polar solvents)
Stabilised) weak base) Nu)
Strong Strong
Strong Strong alkyl halide / NaI / acetone
SN 2 (Good Nu and (Polar aprotic
(Methyl or 1o) (Good LG) alcohol / SOCl2 or PCl3
weak base) Solvents0
Strong alcohol / H2SO4 / heat
o Weak Strong Very Strong
E1 (3 or resonance tertiary alkyl halide / weak base
(weak base) (Good LG) (Polar solvents)
Stabilised) (ROH or H2O)
Strong Strong alkyl halide / KOH / heat,
Strong Strong
E2 (Poor Nu and (Polar aprotic primary alcohols / alcohol /
(3o) (Good LG)
strong base) solvents) H2SO4 / heat
 Nucleophiles (Nu):
- Nucleophile means "nucleus loving" which describes the tendency of an electron rich species to be attracted to
the positive nuclear charge of an electron poor species, the electrophile.
- The more available the electrons, the more nucleophilic the system. Hence the first step should be to locate the
nucleophilic center.
- Nu that contain lone pairs and may be anionic, however the high electron density of a C=C is also a
nucleophile.
- Nucleophilicity trends (compared with basicity)

1. Across a row in the periodic table nucleophilicity (lone pair donation) C- > N- > O- > F- since increasing
electronegativity decreases the lone pair availability. This is the same order as for basicity.
2. If one is comparing the same central atom, higher electron density will increase the nucleophilicity, e.g. an anion
will be a better Nu (lone pair donor) than a neutral atom such as HO > H2O. This is the same order as for
basicity.
3. Within a group in the periodic table, increasing polarisation of the nucleophile as you go down a group enhances
the ability to form the new CX bond and increases the nucleophilicity, so I- > Br- > Cl- > F-. The electron density
of larger atoms is more readily distorted i.e. polarised, since the electrons are further from the nucleus.
 Note that is the opposite order to basicity (acidity increases down a group) where polarisability is much less
important for bond formation to the very small proton.
 Here is a table of relative nucleophilicities as measured in methanol (CH3OH):
Very Good I-, HS-, RS-

Good Br-, HO-, RO-, NC-, N3-
Fair :NH3, Cl-, F-, RCO2-
Weak H2O, ROH
Very Weak RCO2H
- Increasing the Negative Charge Increases Nucleophilicity

 Nucleophiles can be neutral or negatively charged. In either case, it is important that the nucleophile be a good
Lewis base, meaning it has electrons it wants to share. (For example, the O in -OH is negatively charged, but
the O in H2O is neutral.)
- It has been experimentally shown that a nucleophile containing a negatively charged reactive atom is better than
a nucleophile containing a reactive atom that is neutral. For example, when oxygen is part of the hydroxide ion,
it bears a negative charge, and when it is part of a water molecule, it is neutral. The O of OH is a better
nucleophile than the O of H2O, and results in a faster reaction rate. Similarly, when nitrogen is part of NH2, it
bears a negative charge, and when it is part of NH2, it is neutral. The N of NH3 is a better nucleophile than the
N of NH3, and results in a faster reaction rate.
- To say that nucleophilicity follows basicity across a row means that, as basicity increases from right to left on
the periodic table, nucleophilicity also increases. As basicity decreases from left to right on the periodic table,
nucleophilicity also decreases. When it comes to nucleophilicity, do not assign this same rule when making
comparisons between the halogens located in a column. In this case of moving up and down a column,
nucleophilicity does not always follow basicity. It depends on the type of solvent you are using.
- In the section Nucleophilic Substitution, we assigned a relationship to leaving groups containing C, N, O, and
F, showing that the strength of the leaving group follows electronegativity. This is based on the fact that the
best leaving groups are those that are weak bases that do not want to share their electrons. The best
nucleophiles however, are good bases that want to share their electrons with the electrophilic carbon. The
relationship shown below, therefore, is the exact opposite of that shown for the strength of a leaving group.
 Solvents and Nucleophilicity:

-In general solvents as being either polar or nonpolar. Polar solvents can be further subdivided into protic and
and aprotic solvents.
 PROTIC SOLVENTS
- A protic solvent is a solvent that has a hydrogen atom bound to an oxygen or nitrogen. A few examples of
protic solvents include H2O, ROH, RNH2, and R2NH, where water is an example of an inorganic protic
solvent and alcohols and amides are examples of organic solvents.
- Since oxygen and nitrogen are highly electronegative atoms, the O-H and N-H bonds that are present in protic
solvents result in a hydrogen that is positively polarized. When protic solvents are used in nucleophilic
substitution reactions, the positively polarized hydrogen of the solvent molecule can interact with the
negatively charged nucleophile. In solution, molecules or ions that are surrounded by these solvent molecules
are said to be solvated. Solvation is the process of attraction and association of solvent molecules with ions of
a solute. The solute, in this case, is a negatively charged nucleophile.
- When interaction between a protic solvent and a negatively charged nucleophile. The interactions are called
hydrogen bonds.
- The hydrogen bond results from a dipole-dipole force between an electronegative atom, such as a halogen,
and a hydrogen atom bonded to nitrogen, oxygen or fluorine.
- In the case using an alcohol (ROH) as an example of a protic solvent, then interaction can occur with other
solvents containing a positively polarized hydrogen atom, such as a molecule of water, or amides of the form
RNH2 and R2NH.
 IMPORTANT OF SOLVATION
- Solvation weakens the nucleophile; that is, solvation decreases nucleophilicity. This is because the solvent
forms a "shell" around the nucleophile, impeding the nucleophile's ability to attack an electrophilic carbon.
- Furthermore, because the charge on smaller anions is more concentrated, small anions are more tightly
solvated than large anions.
- For example the smaller fluoride anion is represented as being more heavily solvated than the larger iodide
anion. This means that the fluoride anion will be a weaker nucleophile than the iodide anion because fluoride
will not function as a nucleophile at all in protic solvents. It is so small that solvation creates a situation
whereby fluoride's lone pair of electrons are no longer accessible, meaning it is unable to participate in a
nucleophilic substitution reaction.
- Nucleophilicity follows basicity when moving across a row. But, the effect of protic solvents on
nucleophilicity, we learned that solvation weakens the nucleophile, having the greatest effect on smaller
anions. In effect, when using protic solvents, nucleophilicity does not follow basicity when moving up and
down a column. In fact, it's the exact opposite: when basicity decreases, nucleophilicity increases and when
basicity increases, nucleophilicity decreases.
 APROTIC SOLVENTS
- An aprotic solvent is a solvent that lacks a positively polarized hydrogen.
- Aprotic solvents, like protic solvents, are polar but, because they lack a positively polarized hydrogen, they do
not form hydrogen bonds with the anionic nucleophile. The result, with respect to solvation, is a relatively
weak interaction between the aprotic solvent and the nucleophile.
 SUMMARY
 POLAR PROTIC SOLVENTS (polar and ability to be H-bond donor)
o have dipoles due to polar bonds
o can H atoms that can be donated into a H-bond
o examples are the more common solvents like H2O and ROH
o remember basicity is also usually measured in water
o anions will be solvated due to H-bonding, inhibiting their ability to function as Nu
 POLAR APROTIC SOLVENTS (polar but no ability to be H-bond donor)
o have dipoles due to polar bonds
o don't have H atoms that can be donated into a H-bond
o examples are acetone, acetonitrile, DMSO, DMF
o anions are not solvated and are "naked" and reaction is not inhibited
 OVERALL
o All nucleophiles will be more reactive in aprotic than protic solvents
o Those species that were most strongly solvated in polar protic solvents will "gain" the most reactivity in polar
aprotic (e.g. F).
o Polar aprotic solvents are typically only used when a polar protic solvent gives poor results due to having a
weak Nu, (esp. F-, -CN, RCO2-)
 Leaving Groups:
- A leaving group (LG), is an atom (or a group of atoms) that is displaced as stable species taking with it the
bonding electrons. Typically the leaving group is an anion (e.g. Cl-) or a neutral molecule (e.g. H2O).
- The better the leaving group, the more likely it is to depart.
- A "good" leaving group can be recognised as being the conjugate base of a strong acid.
- The Nature of the Leaving Group (LG) depends on electronegativity, size, and resonance.
 As Electronegativity Increases, Basicity Decreases: In general, if we move from the left of the periodic table
to the right of the periodic table as shown in the diagram below, electronegativity increases. As
electronegativity increases, basicity will decrease, meaning a species will be less likely to act as base; that is,
the species will be less likely to share its electrons.
 As Size Increases, Basicity Decreases: In general, if we move from the top of the periodic table to the bottom
of the periodic table as shown in the diagram below, the size of an atom will increase. As size increases,
basicity will decrease, meaning a species will be less likely to act as a base; that is, the species will be less
likely to share its electrons.
Resonance Decreases Basicity: The third factor to consider in determining whether or not a species will be a
strong or weak base is resonance. As you may remember from general chemistry, the formation of a resonance
stabilized structure results in a species that is less willing to share its electrons. Since strong bases, by
definition, want to share their electrons, resonance stabilized structures are weak bases.
- Weak Bases are the Best Leaving Groups
 As mentioned previously, if we move from left to right on the periodic table, electronegativity increases. With
an increase in electronegativity, basisity decreases, and the ability of the leaving group to leave increases. This
is because an increase in electronegativity results in a species that wants to hold onto its electrons rather than
donate them. The following diagram illustrates this concept, showing -CH3 to be the worst leaving group and
F- to be the best leaving group.
 For example, fluoride is such a poor leaving group that SN2 reactions of fluoroalkanes are rarely observed.
 As Size Increases, the Ability of the Leaving Group to Leave Increases: If we move down the periodic table,
size increases. With an increase in size, basicity decreases, and the ability of the leaving group to leave
increases.
 Resonance Increases the Ability of the Leaving Group to Leave: As we learned previously, resonance
stabilized structures are weak bases. Therefore, leaving groups that form resonance structures upon leaving are
considered to be excellent leaving groups. The following diagram shows sulfur derivatives of the type
ROSO3- and RSO3-. Alkyl sulfates and sulfonates like the ones shown make excellent leaving groups. This is
due to the formation of a resonance stabilized structure upon leaving.
 Substrate influence in nucleophilic substitution reactions:

- Sterically Hindered Substrates will reduce the SN2 reaction rate.
- Steric hindrance affects the rate at which an SN2 reaction will occur. As each hydrogen is replaced by an R-group,
the rate of reaction is significantly diminished. This is because the addition of one or two R-groups shields the
backside of the electrophilic carbon, impeding nucleophilic attack.
- Substitutes on Neighboring Carbons Slow Nucleophilic Substitution Reactions, As for example below,
2-methyl-1-bromopropane differ from 1-bromopropane in that it has a methyl group attached to the carbon that
neighbors the electrophilic carbon. The addition of this methyl group results in a significant decrease in the rate of
a nucleophilic substitution reaction. If R groups were added to carbons farther away from the electrophilic carbon,
we would still see a decrease in the reaction rate. However, branching at carbons farther away from the
electrophilic carbon would have a much smaller effect.
 Nucleophilic Substitution Reaction:

 Overall a nucleophilic substitution can be represented as follows:
 There are two fundamental events in a nucleophilic substitution reaction:

i. formation of the new σ bond to the nucleophile
ii. breaking of the σ bond to the leaving group
 Depending on the relative timing of these events, three different mechanisms are possible:
i. Bond breaking to form a carbocation proceeds the formation of the new bond: SN1 reaction
ii. Simultaneous bond formation and bond breaking: SN2 reaction
iii. SNi or Substitution Nucleophilic internal: It stands for a specific but not often encountered nucleophilic
aliphatic substitution reaction mechanism. A typical representative organic reaction displaying this
mechanism is the chlorination of alcohols with thionyl chloride, or the decomposition of alkyl chloroformates,
the main feature is retention of stereo chemical configuration.
 Bonding in the halogen-alkanes
- Halogen-alkanes (also known as halo-alkanes or alkyl halides) are compounds containing a halogen atom
(fluorine, chlorine, bromine or iodine) joined to one or more carbon atoms in a chain.
- The interesting thing about these compounds is the carbon-halogen bond, and all the nucleophilic substitution
reactions of the halogen alkanes involve breaking that bond
 The polarity of the carbon-halogen bonds
- With the exception of iodine, all of the halogens are more electronegative than carbon.
Electronegativity values
C = 2.5 F = 4.0 Cl = 3.0 Br = 2.8 I = 2.5
- That means that the electron pair in the carbon-halogen bond will be dragged towards the halogen end, leaving
the halogen slightly negative (d-) and the carbon slightly positive (d+) except in the carbon-iodine case.
- Although the carbon-iodine bond doesn't have a permanent dipole, the bond is very easily polarised by
anything approaching it. Imagine a negative ion approaching the bond from the far side of the carbon atom:
The fairly small polarity of the carbon-iodine bond will be increased by the same effect
 The strengths of the carbon-halogen bonds
Strengths of various bonds (kJ/mol)

C-H 413
C-F 467
C-Cl 346
C-Br 290
C-I 228
- In all of these nucleophilic substitution reactions, the carbon-halogen bond has to be broken at some point
during the reaction. The harder it is to break, the slower the reaction will be.
- The carbon-fluorine bond is very strong (stronger than C-H) and isn't easily broken. It doesn't matter that the
carbon-fluorine bond has the greatest polarity the strength of the bond is much more important in
determining its reactivity, Therefore expect fluoro-alkanes to be very unreactive and they are.
- In the other halogeno-alkanes, the bonds get weaker as you go from chlorine to bromine to iodine.
- That means that chloro-alkanes react most slowly, bromo-alkanes react faster, and iodo-alkanes react faster
still: Rates of reaction: R-Cl < R-Br < R-I
 Nucleophilic Aliphatic Substitution

1. SN1 Reaction
 The SN1 reaction is a substitution reaction in organic chemistry. "SN" stands for nucleophilic substitution and the
"1" represents the fact that the rate determining step is unimolecular.
 Thus, the rate equation is often shown as having first order dependence on electrophile and zero order
dependence on nucleophile.
 In SN1 reaction, substitution at Sp3 carbon in which a Carbon-Leaving group bond ionizes to form a carbocation
intermediate before the Carbon-Nucleophile bond is formed.
 Making faster SN1 reaction: Use a better leaving group, create a more stable carbocation by increasing number
of carbon groups on Sp3 carbon, or add resonance to structure. Remember that resonance from one pi bonds
outweighs stability from one alkyl group (ex: tertiary without resonance is slower than secondary with
resonance).
 SN1 reaction is:

o Non-stereospecific (attack by nucleophile occurs from both sides)
o Non-concerted - has carbocation intermediate
o Unimolecular - rate depends on concentration of only the substrate.
 Substrate for SN1 reaction:

o Best if tertiary or conjugated (benzylic or allylic) carbocation can be formed as leaving group departs
o never primary
 Formation of carbonium ion.

o Reactivity of an alkyl halide depends chiefly upon how stable a carbonium ion it can form.
o In SN1 reactions the order of reactivity of alkyl halides is Allyl, benzyl >30 >20 >10 >CH3X.
o 30 alkyl halides undergo SN1 reaction very fast because of the high stability of 30 carbocations.
 Nucleophile character in SN1 reaction:

o Best if more reactive (i.e. more anionic or more basic)
 Leaving Group nature:

o Best if more stable (i.e. can support negative charge well)
o Examples: TsO- (very good) > I- > Br- > Cl- > F- (poor)
o However, tertiary or allylic ROH or ROR' can be reactive under strongly acidic conditions to replace OH or
OR.
 Solvent used in SN1 reaction:

o Protic solvents used in SN1 reaction because formation of carbocation intermediate is the rate determining
step. Since for the formation of stable intermediate carbocation highly polar solvent is required. The negative
part of the polar protic solvent interacts with the highly positive part and minimises the energy and makes it
stable.
 SN1 Reaction mechanism:
- For example: The reaction between tert-butylbromide and aqueous sodium hydroxide ion to give
tert-butyl alcohol and bromide ion follows SN1 mechanism.
The Carbon-Halogen (C-Br) bond of the substrates slowly breaks by heterolytic fission
(halogen departs with the shared pairs of electrons) forming a carbocation. This is the
In the first step
slowest step and hence is the rate determining step. The formed carbocation has trigonal
plannar structure.
The nucleophile rapidly attacks the free carbocation giving the product. The nucleophile
In the second step can attack the carbocation from either sides of the plane giving racemized product (with
inversion and retention configuration).
If the leaving group departing from the substrate exists in the form of ion pair with the carbocation, partial
Racemisation occurs.
 Rate of SN1 reaction:

o Rate of SN1 reaction follow first-order rate law.
o According to the kinetics of reactions, their rate depends only on the substrate's concentration [S]:
Reaction rate  [S]
o As for example: hydrolysis of tert-butyl bromide
The overall reaction Mechanism

Step 1: The alkyl halide dissociates to a carbocation and a halide ion.
Step 2: The carbocation formed in step 1 reacts rapidly with water, which acts as a nucleophile. This step
completes the nucleophilic substitution stage of the mechanism and yields an alkyloxonium ion.
Step 3: This step is a fast acid–base reaction that follows the nucleophilic substitution. Water acts as a base to
remove a proton from the alkyloxonium ion to give the observed product of the reaction, tert-butyl alcohol.
 SN1 reaction with Alky Shift:
 SN1 reaction with Alky Shift leads to ring expansion:

 It doesn’t always have to be a methyl group that moves. One interesting example is when a carbocation is
formed adjacent to a strained ring, such as a cyclobutane. Even though the CH3 could potentially migrate in
this case, it’s favourable to shift one of the alkyl groups in the ring, which leads to ring expansion and the
formation of a less strained, five membered ring.
 Stereochemistry in SN1 reaction:

o In SN1 reaction, the nucleophile attacks the planar carbocation. Since there is an equally probability of attack
on each face there will be a loss of stereochemistry at the reactive center as both products will be observed.
o SN1 reaction proceeds with racemization though may not be complete.
 SN1 mechanism for reaction of alcohols with HBr
Step 1:
An acid/base reaction. Protonation of the alcoholic oxygen
to make a better leaving group. This step is very fast and
reversible. The lone pairs on the oxygen make it a Lewis
base.
Step 2:
Cleavage of the CO bond allows the loss of the good
leaving group, a neutral water molecule, to give a
carbocation intermediate. This is the rate determining step
(bond breaking is endothermic)
Step 3:
Attack of the nucleophilic bromide ion on the electrophilic
carbocation creates the alkyl bromide.
 SN1 mechanism for reaction of alkyl halides with H2O
Step 1:
Cleavage of the already polar C-Br bond
allows the loss of the good leaving group, a
halide ion, to give a carbocation intermediate.
This is the rate determining step (bond
breaking is endothermic)
Step 2:
Attack of the nucleophile, the lone pairs on
the O-atom of the water molecule, on the
electrophilic carbocation creates an oxonium
species.
Step 3:
Deprotonation by a base yields the alcohol as
the product.
o Note that this is the reverse of the reaction
of an alcohol with HBr.
o In principle, the nucleophile here, H2O,
could be replaced with any nucleophile, in
which case the final deprotonation may
not always be necessary.
2. SN2 Reaction
 SN2 reaction stands for Substitution Nucleophilic Bimolecular Reaction.

 In this mechanism, one bond is broken and one bond is formed synchronously, i.e., in one step.
 The SN2 mechanism begins when an electron pair of the nucleophile attacks the back lobe of the leaving group.
Carbon in the resulting complex is trigonal bipyramidal in shape. With the loss of the leaving group, the carbon
atom again assumes a pyramidal shape; however, its configuration is inverted.
 In an SN2 reaction, Nucleophile attacks opposite side of the leaving group. This occurs because the nucleophilic
attack is always on the back lobe (antibonding orbital) of the carbon atom acting as the nucleus. The bond between
nucleophile (Nu) and carbon (C) forms at the exact same time that the bond between carbon and Leaving Group
(L) breaks. In other words, Nu-C bond formation and C-Leaving Group bond breakage happen simultaneously. In
the transition state, the carbon is partially attached to both.
 SN2 mechanisms always proceed via rearward attack of the nucleophile on the substrate. This process results in the
inversion of the relative configuration, going from starting material to product. This inversion is often called the
Walden inversion.
 Steric hindrance: SN2 reactions require a rearward attack on the carbon bonded to the leaving group. If a large
number of groups are bonded to the same carbon that bears the leaving group, the nucleophile's attack should be
hindered and the rate of the reaction slowed. This phenomenon is called steric hindrance. The larger and bulkier
the group(s), the greater the steric hindrance and the slower the rate of reaction.
Effect of Steric Hindrance upon Rates of SN2 Reaction

Alkyl Group Relative Rate of Substitution
-CH3 (small group) 30
-CH2CH3 (large group) 1
-CH(CH3)2 (bulky group) 0.03
-C(CH3)3 (very bulky group) 0
0
SN2 reactions give good yields on 1 (primary) alkyl halides,
moderate yields on 20(secondary) alkyl halides, and poor to no
yields on 30 (tertiary) alkyl halides.
 The Rate of SN2 Reaction
- The rate of the reaction depends on the concentration of both the Substrate [S] and the Nucleophile [Nu] and
the reaction is of second order and is represented as SN2. Rate  [Substrate] [Nucleophile]
- SN2 Mechanism: a substitution at an sp3 carbon in which the nucleophile-carbon bond formation and the leaving
group-carbon bond breakage occur at the same time.
- Transition state: highest point of an energy structure on a reaction profile graph for any mechanism step
- SN2 reactions are bimolecular, meaning the rate-determining step involves the nucleophile and the starting
molecule (electrophile).
- For an SN2 reaction, the rate-determining step occurs when the nucleophile attacks the sp3 carbon and the
leaving group leaves. As depicted on the graph to the right, the energy barrier of the transition state of the
nucleophile carbon bond formation and the carbon-leaving group bond scission must be overcome for the
reaction to occur.
Energy Profile of the reaction
 Factors affecting the rates of SN2 reactions:
1. Structure of Substrate
- In SN2 reaction the substrate plays the most important part in determining the rate of the reaction.
- This is because the nucleophile attacks from the back of the substrate, thus breaking the carbon leaving group
bond and forming the carbon nucleophile bond. Therefore, to maximise the rate of the S N2 reaction, the back of
the substrate must be as unhindered as possible.
- Overall, this means that methyl and primary substrates react the fastest, followed by secondary substrates.
- Tertiary substrates do not participate in SN2 reactions, because of steric hindrance
2. The Nature of the Nucleophile
- For SN2 reaction in solution there are some principles that govern the effect of nucleophile on the rate.
- A nucleophile with a negative charge is always more powerful than its conjugate acid. Thus OH¯ is more
powerful than H2O, NH2¯ is more powerful than NH3, CH3O¯ is more powerful than CH3OH, etc.
- In comparing nucleophiles whose attacking atom is in the same row of the periodic table, nucleophilicity is
approximately in order of basicity as following:
NH2¯> RO¯ > OH¯> NH3 > F¯> H2O
R3C¯ > R2N¯ > RO¯ > F¯
- Going down the periodic table, nucleophilicity increases, though basicity decreases. Thus the usual order of
halide nucleophilicity is: I¯ > Br¯ > Cl¯ > F¯
- So, a strong/anionic nucleophile always favours SN2 manner of nucleophilic substitution.
3. Effect of Solvent
- Polar aprotic solvent (without OH) favors SN2.

- For examples of polar aprotic solvents are acetone, dimethylsulfoxide, N,N’-dimethylformamide, etc.
- In SN2 reaction, freer the nucleophile, faster is the reaction.
- The stronger the solvation of the nucleophile, the greater the energy required to remove the nucleophile from its
solvation cage to reach the transition state, and hence lower is the rate of the SN2 reaction.
- For example when NaOH is added to aprotic solvent like acetone or dimethyl sulfoxide, sodium is solvated by
the solvent whereas OH¯ is not. Thus the nucleophile is free and can easily attack the positively charged carbon
for SN2.
- In polar protic solvent both the sodium and hydroxide ions are strongly solvated and more energy is needed to
free the nucleophile from the solvent cage to carry out SN2.
4. The nature of the leaving group
- The ability of leaving group is related to how stable it is as an anion.

- The most stable anions and the best leaving group are the conjugate bases of strong acid i.e., are weaker bases.
Conversely, poor leaving groups form ions of poor to moderate stability.
- Strong bases, such as OH¯, NH2¯, and RO¯, make poor leaving groups. Water, which is less basic than a
hydroxide ion, is a better leaving group.
- Some good leaving groups are the sulfate ion and the p-toluenesulfonate (tosylate ion). The following list ranks
atoms and molecules in order of their stability as leaving groups, from most to least stable.
 The SN2 Mechanism of Nucleophilic Substitution
The Overall Reaction
The reaction proceeds in a single step. Hydroxide ion acts as a nucleophile. While the C⎯Br
The Mechanism
bond is breaking, the C⎯O bond is forming.
The Transition State Hydroxide ion attacks carbon from the side opposite the C⎯Br bond
Carbon is partially bonded to both hydroxide and bromide. The arrangement of bonds undergoes
tetrahedral inversion from as the reaction progresses.
 Nucleophiles and Nucleophilicity:
- The Lewis base that acts as the nucleophile often is, but need not always be, an anion. Neutral Lewis bases such
as amines (R3N:), phosphines (R3P:), and sulfides (R2S ¨:) can also serve as nucleophiles.
- Other common examples of substitutions involving neutral nucleophiles include solvolysis reactions-
substitutions where the nucleophile is the solvent in which the reaction is carried out. Solvolysis in water
(hydrolysis) converts an alkyl halide to an alcohol. The reaction occurs in two steps. The first yields an
alkyloxonium ion by nucleophilic substitution and is rate-determining. The second gives the alcohol by proton
transfer-a rapid Bronsted acid-base reaction.
- Solvolysis in methanol (methanolysis) gives a methyl ether.
Nucleophilicity of Some Common Nucleophiles

Reactivity class Nucleophile Relative reactivity
Very good nucleophiles I–, HS–, RS– >105
– – – – –
Good nucleophiles Br , HO , RO , CN , N3 104
Fair nucleophiles NH3, Cl–, F–, RCO2– 103
Weak nucleophiles H2O, ROH 1
Very weak nucleophiles RCO2H 10–2
3. Comparison of SN1 and SN2
Points SN1 SN2

Steps Two steps One step
Unimolecular, only substrate is Bimolecular, both substrate and nucleophile are
Molecularity
involved in rate determining step involved in the reaction
Kinetics and rate First order Second order
Racemisation or partial racemization
Stereochemistry favouring product with inverted Complete inversion
configuration
Effect of substrate Stability of carbocation: Steric hindrance decreases the rate of reaction:
structure on rate Tertiary > secondary > primary > methyl Methyl > primary > secondary > tertiary
Effect of solvents on Polar protic solvents like water favours Polar aprotic solvent (without OH) favours SN2,
rate SN1. like acetone, DMSO
Nucleophilicity and Weak nucleophiles of low
Stong nucleophles of high concentration
concentration of concentration too can make the reaction to increases the rate
nucleophiles occur
Weakly basic and highly polarizable group Weakly basic and highly polarizable group
Leaving group effect
increase the rate increases the rate.
Reaction
carbocation None
intermediate
Competition E1 (Elimination Unimolecular) and
E2 (Elimination Bimolecular)
Reaction rearrangement
 Note By: Classification of Solvents

Solvent is a liquid substance capable to dissolve other substances (solutes) without chemical changes.
1. Molecular structure of solvents
2. Inorganic solvents
3. Organic solvents
1. MOLECULAR STRUCTURE OF SOLVENTS
- Ability of a substance to dissolve another substance is determined by compatibility of their molecular structures
(like dissolves like). Types of molecular structures of the solvents are as follows:
(i) Polar protic solvents
 A polar protic molecule consists of a polar group OH and a non-polar tail.
 The structure may be represented by a formula R-OH.
 Polar protic solvents dissolve other substances with polar protic molecular structure. Polar protic solvents are
miscible with water (hydrophilic).
 Examples of polar protic solvents: water (H-OH), acetic acid (CH3CO-OH), methanol (CH3-OH), ethanol
(CH3CH2-OH), n-propanol (CH3CH2CH2-OH), n-butanol (CH3CH2CH2CH2-OH).
(ii) Dipolar aprotic solvents

 Dipolar aprotic molecules possess a large bond dipole moment (a measure of polarity of a molecule chemical
bond).
 They do not contain OH group.
 Examples of dipolar aprotic solvents: acetone [(CH3)2C=O], ethyl acetate (CH3CO2CH2CH3), dimethyl
sulfoxide [(CH3)2SO], acetonitrile (CH3CN), dimethylformamide [(CH3)2NC(O)H].
(iii) Non-polar solvents
 Electric charge in the molecules of non-polar solvents is evenly distributed; therefore the molecules have low
dielectric constant.
 Non-polar solvents are hydrophobic (immiscible with water).
 Non-polar solvents are lipophilic as they dissolve non-polar substances such as oils, fats, greases.
 Examples of non-polar solvents: carbon tetrachloride (CCl4), benzene (C6H6), and diethyl ether
(CH3CH2OCH2CH3), hexane [CH3(CH2)4CH3], methylene chloride (CH2Cl2).
2. INORGANIC SOLVENTS
- The most popular inorganic (not containing carbon) solvents are water (H 2O) and aqueous solutions containing
special additives (surfacants, detergents, PH buffers, inhibitors).
- Other inorganic solvents are liquid anhydrous Ammonia (NH3), concentrated sulfuric acid (H 2SO4), sulfuryl
chloride fluoride (SO2ClF).
3. ORGANIC SOLVENTS
(i) Oxygenated solvents
- Oxygenated solvent is an organic solvent, molecules of which contain oxygen.
- Oxygenated solvents are widely used in the paints, inks, pharmaceuticals, fragrance sectors, adhesives,
cosmetics, detergents, food industries. Examples of oxygenated solvents: alcohols, glycol ethers, methyl
acetate, ethyl acetate, ketones, esters, and glycol ether/esters.
(ii) Hydrocarbon solvents

- Molecules of hydrocarbon solvents consist only of Hydrogen and carbon atoms.
 Aliphatic solvents: Molecules of aliphatic solvents have straight-chain structure. Hexane, gasoline,
kerosene are aliphatic solvents. -White spirits
 White spirit (mineral turpentine spirits): It is a mixture of aromatic and paraffinic hydrocarbons.
 Pure aromatic solvents: Molecules of pure aromatic solvents have benzene ring structure. Examples of
pure aromatic solvents are benzene, toluene and xylene.
(iii) Halogenated solvents

- Halogenated solvent is an organic solvent, molecules of which contain halogenic atoms: chlorine (Cl),
fluorine (F), bromine (Br) or iodine (I).
- Accordingly to the type of halogen halogenated solvents are classified into the following categories:
 Chlorinated solvents: The common chlorinated solvents are trichlorethylene (ClCH-CCl2), perchlorethylene
(tetrachlorethylene, Cl2C-CCl2), methylene chloride (CH2Cl2), carbon tetrachloride (CCl4), chloroform
(CHCl3), 1,1,1-trichlorethane (methyl chloroform, CH3-CCl).
 Fluorocarbon solvents: Examples of fluorocarbon solvents: dichlorofluoromethane (freon 21, CHCl 2F),
trichlorofluoromethane (freon 11, CCl3F), tetrafluoromethane (freon 14, CF4), difluorodichloromethane (freon
12, CHCl2F2), hydrochlorofluorocarbon (freon 22, HCFC).
 Brominated solvents: Examples of brominated solvents: ethylene dibromide (1,2-dibromoethane, BrCH2-
CH2Br), methylene chlorobromide (bromochloromethane, CH2BrCl), methyl bromine (bromomethane,
CH2Br).
 Iodinated solvents: Examples of iodinated solvents: n-butyl iodide (1-iodobutane, CH3CH2CH2CH2I), methyl
iodide (iodomethane, CH3I), ethyl iodide (iodoethane, C2H5I), n-propyl iodide (1-iodopropane, CH3CH2CH2I).
 Note By: 1,2-Alkyl Shift
 A 1,2-alkyl shift is a carbocation rearrangement in which an alkyl group migrates to the carbon atom bearing
the formal charge of +1 (Carbon 2) from an adjacent carbon atom (Carbon 1).
 Note By: 1,2-Aryl Shift

 A 1,2-aryl shift is a carbocation rearrangement in which an aryl group in a carbocation migrates to the carbon
atom bearing the formal charge of +1 (Carbon 2) from an adjacent carbon atom (Carbon 1).
 Note By: 1,2-Hydride Shift

 A 1,2-hydride shift is a carbocation rearrangement in which a hydrogen atom in a carbocation migrates to the
carbon atom bearing the formal charge of +1 (Carbon 2) from an adjacent carbon (Carbon 1).
 Note By: Alky Shift leads to ring expansion
 It doesn’t always have to be a methyl group that moves. One interesting example is when a carbocation is
formed adjacent to a strained ring, such as a cyclobutane. Even though the CH3 could potentially migrate in
this case, it’s favourable to shift one of the alkyl groups in the ring, which leads to ring expansion and the
formation of a less strained, five membered ring.
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ADVANCED ORGANIC CHEMISTRY -I (MPC 102T) UNIT-I: Basic Aspects of

Presentation · August 2019

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Addition of chlorine to ethylene

Electrophilic addition to alkene

Nucleophilic addition of nucleophile to carbonyl

Free radical addition of halide to alkene

Elimination reaction of cyclohexanol to cyclohexene with sulfuric acid and heat

- Substitution and elimination reactions are strongly influenced by:

- Nucleophilicity trends (compared with basicity)

Very Good I-, HS-, RS-

- Increasing the Negative Charge Increases Nucleophilicity

 Solvents and Nucleophilicity:

 Substrate influence in nucleophilic substitution reactions:

 Nucleophilic Substitution Reaction:

 There are two fundamental events in a nucleophilic substitution reaction:

 The strengths of the carbon-halogen bonds

Strengths of various bonds (kJ/mol)

 Nucleophilic Aliphatic Substitution

 SN1 reaction is:

 Substrate for SN1 reaction:

 Formation of carbonium ion.

 Nucleophile character in SN1 reaction:

 Leaving Group nature:

 Solvent used in SN1 reaction:

 SN1 Reaction mechanism:

 Rate of SN1 reaction:

The overall reaction Mechanism

 SN1 reaction with Alky Shift:

 SN1 reaction with Alky Shift leads to ring expansion:

 Stereochemistry in SN1 reaction:

 SN1 mechanism for reaction of alcohols with HBr

 SN1 mechanism for reaction of alkyl halides with H2O

 SN2 reaction stands for Substitution Nucleophilic Bimolecular Reaction.

Effect of Steric Hindrance upon Rates of SN2 Reaction

 The Rate of SN2 Reaction

Energy Profile of the reaction

2. The Nature of the Nucleophile

- Polar aprotic solvent (without OH) favors SN2.

4. The nature of the leaving group

- The ability of leaving group is related to how stable it is as an anion.

 The SN2 Mechanism of Nucleophilic Substitution

The Overall Reaction

 Nucleophiles and Nucleophilicity:

- Solvolysis in methanol (methanolysis) gives a methyl ether.

Nucleophilicity of Some Common Nucleophiles

3. Comparison of SN1 and SN2

Points SN1 SN2

 Note By: Classification of Solvents

(ii) Dipolar aprotic solvents

(ii) Hydrocarbon solvents

(iii) Halogenated solvents

 Note By: 1,2-Alkyl Shift

 Note By: 1,2-Aryl Shift

 Note By: 1,2-Hydride Shift

 Note By: Alky Shift leads to ring expansion

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