Organic Reactions
Part-1
Substitution and Elimination
By
Dr. Ishita Sanyal
Chemistry Department, TMSL
Types
● Substitution Reaction
● Elimination Reaction
● Addition Reaction
● Oxidation Reaction
● Reduction Reaction
● Rearrangement Reaction
● Ring Closing Reaction
● Ring Opening Reaction
Nucleophilic Substitution
SN1 (Substitution Nucleophilic Unimolecular)
SN2 (Substitution Nucleophilic Bimolecular)
SNi (Substitution Nucleophilic Internal)
NGP (Neighbouring Group Participation)
1
SN Mechanism
Features of SN1:
❖ Unimolecular reaction
❖ Two step process. First step is r.d.s.
❖ Rate depends only on concentration of substrate
❖ Associated with Racemization
SN1 reaction is preferred by
❖ 3o, allyl, benzyl substrate
❖ Poor nucleophile (H2O, ROH)
❖ Polar protic solvent (H2O, ROH)
❖ Good leaving group
❖ Why Racemization?
As the intermediate carbocation is planar, nucleophile can attack
from both direction with equal probability causing racemization.
❖ Why 3o, allyl, benzyl substrate?
As the intermediate carbocation is highly stabilised
❖ Why poor nucleophile?
As the rate does not depend on strength of nucleophile because it
comes after rate determining step
❖ Why polar protic solvent?
As carbocation and negatively charged leaving group both are
stabilised by polar protic solvent like alcohol, H2O
❖ Why good leaving group?
As with good leaving group carbocation formation is favoured
1
Solvent effect in SN
Polar protic solvent solvates both carbocation and the leaving group.
SN2 Mechanism
Features of SN2
❖ Bimolecular reaction
❖ Single step process
❖ Rate depends on substrate and nucleophile
❖ Associated with Inversion of Configuration
SN2 reaction is preferred by
❖ 1o substrate
❖ Strong nucleophile (OH-, RO-, N3-, I-)
❖ Polar aprotic solvent (DMF, DMSO, CH3CN)
❖ Good leaving group (-OTs, I-)
❖ Why Inversion of Configuration?
● As the nucleophile attack from backside
❖ Why 1o substrate?
● As the transition state is having high steric strain,
❖ Why strong nucleophile?
● As the nucleophile is involved in rate determining step, stronger the
nucleophile higher is the rate of reaction
❖ Why polar aprotic solvent?
● As in polar aprotic solvent positive counterpart of nucleophile is
solvated and the nucleophile is free to attack the substrate
❖ Why good leaving group?
● As with good leaving group reaction occurs at a faster rate
Nucleophilicity of reagent
❖ Charge: For similar species, the species with negative charge is
always a stronger nucleophile than a neutral species.
OH- >H2O, NH2- > NH3
❖ Electronegativity: A more electronegative element holds more
tightly its valence electrons, which makes it a weaker nucleophile.
Hence, from left to right within a row of the periodic table nucleophilic
strength decreases.
CH3- > NH2- > OH- > F-
❖ Polarizability: Larger atoms are more polarizable, i.e. their
electron clouds are more “flexible”, which makes the approach to
substrate and the bonding an overall energetically easier process.
Hence, from top to bottom within a group in the periodic table the
nucleophilic strength increases.
I- > Br- > Cl- > F-
❖ Steric hindrance: Orbitals at carbon that participate in reactions
are generally less accessible than protons are. An effect called
“steric hindrance” comes into play. Bulkier a given nucleophile is,
the slower the rate of its reactions.
Ambident nucleophile
Explanation
❖ KNO2 is predominantly ionic and one of the oxygen atom
have a negative charge. Nucleophilic attack by this
negatively charged oxygen on alkyl halide gives alkyl
nitrite.
❖ In contrast, AgNO2 is a covalent compound and both
oxygen and nitrogen atoms carry lone pair of electrons.
Since nitrogen is less electronegative than oxygen,
therefore lone pairs on nitrogen is more easily available
for bond formation. So nitroalkanes are chief product.
Solvent effect in SN2
They do solvate strongly the positive counter-ion,
producing essentially “free” anion nucleophiles, whose
reactivity is even higher. Conclusion: Polar aprotic
solvents tend to accelerate SN2 reaction with
negatively charged nucleophiles.
Leaving Group
A good leaving group needs to be a stable anion that are
weak bases which can delocalize charge
Example: Leaving group ability of halogens follow the
order I- > Br- > Cl- > F-
-OTs is another very good leaving group.
SNi Reaction
Alcohol to chloride conversion with SOCl2 reagent occurs with
retention of configuration.
Mechanism:
In presence of Pyridine with SOCl2, inversion of configuration
occurs through SN2 reaction
Elimination
E1: Elimination unimolecular
E2: Elimination Bimolecular
E1cB: Elimination unimolecular conjugate base
E1 Mechanism
Features of E1:
❖ Unimolecular reaction
❖ Two step process. First step is r.d.s.
❖ Rate depends only on concentration of substrate
E1 reaction is preferred by
❖ 3o substrate
❖ Weak base (H2O, ROH)
❖ Polar protic solvent (H2O, ROH)
❖ Good leaving group
E2 Mechanism
Features of E2:
❖ Bimolecular reaction
❖ One step concerted process.
❖ Rate depends on concentration of substrate and base
E2 reaction is preferred by
❖ 3o substrate
❖ Strong base in high concentration (EtO-, tBuO-)
❖ Polar aprotic solvent (DMF, DMSO)
❖ Good leaving group
Zaitsev rule: More substituted alkene is the
major product.
Why more substituted alkene?
Hofmann Elimination
In elimination reactions involving charged leaving
group, least substituted alkene is the major product.
Why least substituted alkene?
NMe3+ group is poor leaving group. Also it has high electronegativity and
makes both β-protons highly acidic. So the protons are readily abstracted by
base while leaving group does not depart. Transition states are carbanion like.
TS1 is destabilized by +I effect of adjacent methyl group while in TS2 there is
no such destabilizing effect. So TS2 is more stable and leads to less substituted
product.
TS1 TS2
Conditions of Hofmann Elimination
❖ Substrate contains poor leaving group with
high elecronegativity
(e.g. –F, -NMe3+, -SMe2+)
❖ Hindered base is used (e.g. tBuO-)
E1cB Mechanism
Features of E1cB:
❖ Unimolecular reaction
❖ Two step process. Second step is r.d.s.
❖ Carbanion intermediate is formed which is conjugate
base of substrate
❖ Rate depends on concentration of substrate and base
E1cB reaction is preferred by
❖ Substrate containing highly acidic hydrogen that is
removed by base
❖ Leaving group is poor (-F, -OH, -OR)
Synthetic utility of E1cB
● Dehydration of aldol
Substitution vs Elimination
● 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
Important Points
1. The strength of the nucleophile/base determines the order of the
reaction.
If a strong nucleophile or base is present, it will likely force second
order kinetics (SN2 or E2.)
2. Primary halides usually undergo the SN2 reaction, sometimes
the E2 reaction.
● With good nucleophiles, SN2 substitution is usually observed.
● With a very strong base present, E2 elimination may also be
observed
● For E2 on a primary, unbranched alkyl halide, use tert-butoxide
● If the alkyl group on the primary halide is very bulky (it has
β-branching), theSN2 reaction may be slowed enough that more
elimination will be observed.
3. Tertiary halides usually undergo the E2 reaction (w/ strong
base) or a mixture of E1 and SN1 (w/ weak base and PP solvent)
A strong base forces 2nd order kinetics, resulting in elimination
by the E2 mechanism. In the absence of a strong base, tertiary
halides react by first order processes, giving a mixture of SN1 and
E1. The reaction conditions determine the ratio of substitution to
elimination, with high temperatures favoring elimination. If the
elimination product has three or more R-groups bonded to the
alkene, E1 is usually favored.
4. The reactions of secondary alkyl halides are more difficult to
predict!
● Secondary alkyl halides undergo SN1, SN2, E1 and E2.
● Strong nucleophiles that are weak bases will promote the SN2
reaction.
● Strong nucleophiles that are strong bases will promote the E2
reaction.
● Weak nucleophiles/bases will promote the SN1/E1 reaction.
