Chapter 6: Nucleophilic Substitution and Elimination

Reactions of Alkyl Halides  Low solubilities in water

 Miscible to nonpolar solvents and weakly polar
Halogens - organic solvents
1. Fluorine (F) -gas, smallest  Many Chloroalkanes are toxic and carcinogenic
2. Chlorine (Cl) - gas
3. Bromine (Br) - liquid II. Nucleophilic Substitution reactions
4. Iodine (I) – solid , largest  A nucleophile (Nu:) displaces a leaving group
5. Astatine (At) - solid (LG) in the molecule that undergoes the
6. (and sometimes) Tennessine (Ts) – a synthetic, very substitution (the substrate)
unstable element – solid

Key Characteristics:
 Highly reactive — especially with metals, forming
salts (e.g., NaCl or table salt).
 Exist as diatomic molecules in their natural state
(e.g., F₂, Cl₂).
 Reactivity decreases down the group (Fluorine is
the most reactive).
Down the Size increases
Periodic Table Bond Length Increases
Carbon-halogen bond strength
decreases

 Boiling points increase with heavier halogens for

the same alkyl group
 Most nucleophiles are anions, but nucleophiles can
 Boiling points increase with larger alkyl groups for
also be neutral molecules (such as the last example).
the same halogen
 The key idea is that a nucleophile is any species
 Branching lowers boiling point slightly (because it
that donates a lone pair of electrons to form a new
reduces surface area → weaker van der Waals
bond — it doesn’t have to be negatively charged.
forces)
 Any negative ion or uncharged molecule with an
 Density increases with heavier halogens
unshared electron pair is a potential nucleophile.
 For the same halogen, branched groups tend to
 Heterolytic Bond Cleavage - a type of bond
have slightly lower densities than straight-chain
breaking where the electron pair goes to one atom
groups
 Fluoromethane – highly polar, shortest and
Strongest C-X bond
III. Nucleophiles
 Iodomethane – less polar, longest and weakest C-X
1. Negatively Charged Nucleophile = neutral product
bond
2. Neutral Nucleophile = initially positively charged
Alkyl Halide- has halogen atom bonded to an sp3-
product
hybridized (tetrahedral) carbon atom

 polarized because the halogen is more

electronegative than carbon.
 primary (1°) – one carbon attached to the halogen-
carbon
 secondary (2°) - one carbon attached to the
halogen-carbon
 tertiary (3°) - one carbon attached to the halogen-
carbon
 A neutral nucleophile initially gives 2 products (one
positive), but to become neutral, the system ends
up with 3 total products after proton transfer.
 Neutral nucleophiles are often solvents molecules
 Solvolysis - A reaction in which the solvent itself
acts as the nucleophile and breaks a bond in the
substrate (usually an alkyl halide).
Alkenyl Halides - Alkene + Halogen
IV. Leaving Groups
 vinylic halides
Aryl Halides – Aromatic Ring + Halogen
 A good leaving group is a substituent that can leave
Phenyl Halides – Benzene + Halogen
as a relatively stable, weakly basic molecule or ion.
 For an LV to be neutral after the separation, it must
I. Physical Properties of Alkyl Halides
be positive while bonded
 The positive charge on a leaving group (like that
above) usually results from protonation of the
substrate by an acid.
 Possible only when the nucleophile is not strongly
basic, and is present in abundance

V. Kinetics of a Nucleophilic Substitution Reaction

Kinetics- rate of a reaction

 Measured experimentally VII. Temperature and Reaction Rate

A. SN2 Reaction (Substitution Nucleophilic,  Most Chemical reactions occur much more rapidly
Bimolecular) at higher temperatures
 Fewer collisions result in successful reactions.
 Bond breaking and bond forming happen  More collisions mean faster reaction rate.
simultaneously — in one concerted step. One-
Step Process
 Brief partial bonding of the nucleophile and B. SN1 Reaction (Substitution Nucleophilic,
leaving group on opposite sides (Transition Unimolecular)
State)
 Backside Attack- when the nucleophile  Order: First Order Overall
approaches the carbon atom from the side  Unimolecular
opposite to the leaving group.  Multi-Step Reaction:
 The stereochemistry inverts (Inversion of o Rate Determining Step – Carbocation
Configuration) (sp2, trigonal planar)
 Order: Second Order Overall tells us that: - requires heterolytic cleavage
o The speed of the reaction depends on both - endothermic (Bond breaking)
reactants. o Transition State
o If you double the concentration of either
reactant, the rate doubles. VIII. Relative Stabilities of Carbocations
o If you double both, the rate quadruples
(because 2 ×2=4 ).  Tertiary carbocations are the most stable, and the
methyl carbocation is the least stable

 Bimolecular - two species are involved in the

step whose rate is being measured

VI. Transition State Theory

Term What it measures Symbol Focus

Exothermic / Heat (enthalpy) Thermal energy — is heat released or
ΔH
Endothermic change absorbed?  Hyperconjugation – electron delocalization
Exergonic / Free energy Total usable energy — is the reaction
Endergonic change
ΔG
spontaneous? - a system is stabilized

 Large equilibrium constant (K) - Means the reaction

goes to completion — products are strongly IX. Racemization
favored. - “a process by which an optically active substance
 Free-Energy Diagram either dextro (CW) or levorotatory(CCW), is directly
o Reaction Coordinate - represents the converted into a racemate”
progress of the reaction (conversion of - takes place whenever the reaction causes chiral
reactants to products). molecules to be converted to an achiral intermediate.
o Top of the Energy Curve- Corresponds to
the Transition State (‡) — the highest  Racemic/Racemate- a mixture of equal amounts of
energy point. two enantiomers (mirror-image forms) of a chiral
o Free Energy of Activation (ΔG‡)- The compound.
energy difference between reactants and  Enantiomers- type of stereoisomer—molecules that
the transition state. have the same molecular formula and connectivity
- Determines reaction rate (how fast it but differ in the 3D arrangement of atoms.
occurs).  Chirality- Chirality is defined as “an object which is
o Free-Energy Change (ΔG°)- The energy asymmetric and cannot be superimposed over its
difference between reactants and products. mirror image is known as chiral or stereocenter”.
- Determines reaction spontaneity
(whether it proceeds favorably).
 Complete Racemization - If the original compound
loses all of its optical activity in the course of the 1) nucleophiles with a negative charge are more
reaction reactive than their neutral counterparts because
they are more electron-rich and attack electrophiles
X. Solvolysis (hydrolysis for water, methanolysis more readily.
for methanol) 2) Stronger bases are also stronger nucleophiles for
- OH attaches to the substrate, H attaches to the the same attacked atom
halogen creating an acid 3) When the nucleophilic atoms are different,
nucleophilicity doesn’t always follow basicity.

XI. Factors affecting the Rates of SN1 and SN2

Reactions C. The Effects of the Solvent
1. The structure of the substrate  SN2 reactions are favored by polar aprotic solvents
2. The concentration and reactivity of (e.g., acetone, DMF, DMSO).
the nucleophile (for SN2 reactions  SN1 reactions are favored by polar protic solvents
only) (e.g., EtOH, MeOH, H2O).
3. The effect of the solvent
4. The nature of the leaving group  Polar Protic Solvents
- has hydrogen bonds, FON
A. The Effect of the Structure of the Substrate - facilitate the formation of a carbocation by
forming hydrogen bonds with the leaving group
SN2 Reactions - dielectric constant, a measure of the solvent’s
ability to insulate opposite charges
 Steric Effect - effect on the relative rates caused by
the space-filling properties of those parts of a
molecule attached at or near the reacting site. - Hydrogen bonding strength depends on ion size:
 Steric Hindrance - when the spatial arrangement of  Smaller ions (like F⁻) have higher charge density
atoms or groups at or near a reacting site of a → form stronger hydrogen bonds → more
molecule hinders or retards a reaction. strongly solvated → less reactive.
 Least reactive –neopentyl  Larger ions (like I⁻) have lower charge density →
 Don’t react - tertiary substrates weaker hydrogen bonds → less solvated →
 No SN2 reaction on sp2 or sp more reactive.
- SN1 reactions are faster because the solvents
stabilize the ionic intermediates

 Polar Aprotic Solvents

- have strong dipoles but do not have OH or NH
groups
SN1 Reactions The anions remain “naked” (free and unsolvated)
 Primary Factor: Relative Stability of the - the trend depends mainly on basicity, and since F⁻
Carbocation formed is the strongest base, it also becomes the best
nucleophile.
 Nucleophile does not participate in the rate - SN2 reactions are faster because nucleophiles are
determining step naked and reactive

B. The Effects of the Concentration and Strength of

the Nucleophile

SN2 Reactions D. The Nature of the Leaving Group

 Affected by both the concentration and identity of  The best leaving groups are those that become a
the attacking nucleophile relatively stable anion or a neutral molecule when
 Nucleophilicity- the relative strength of a they depart.
nucleophile measured via the rate of its SN2  because it stabilizes the negative charge forming on
reaction it during the transition state, reducing the activation
- good nucleophile reacts rapidly in an SN2 reaction energy.
SN1 Reactions  The weaker the base (after they depart), the better
 Not Affected by either concentration of the identity the leaving group
of the nucleophile - because the nucleophile does  Because they are stable on their own, are not
not participate in the rate- determining step craving for +, it’s easier to leave.
 Ex. Of Strong bases, poor LG : H-, CH3-, R–F, R–OH,
R–NH₂, and R–OR′
 The relative strengths of nucleophiles can be
correlated with three structural features:
 Ex. Of Strong Bases, good LG: I⁻, Br⁻, Cl⁻, TsO⁻, - a base removes a β hydrogen from the β carbon as
alkane sulfonate ions, alkyl sulfate ions, and the p- the double bond forms and a leaving group departs
toluenesulfonate ion from the α carbon.
 Trifluoromethanesulfonate ion CF3SO3- is one of - Bimolecular
the best leaving groups known. - Second Order Overall
- Has one transition state
XII. Organic Synthesis: Functional Group - The five atoms involved in the transition state of an
Transformations using SN2 Reactions E2 reaction (including the base) must be coplanar,
 Functional Group Transformation/ Functional Group that is, lie in the same plane.
Introconversion
 Alkyl iodides by nucleophilic substitution reactions.
B. Unimolecular Elimination (E1)
- has a rate-determining step
XIII. The Unreactivity of Vinylic and Phenylic Halides - Unimolecular
 Alkenyl and phenyl halides are generally unreactive - First Order Overall
in SN1 or SN2 reactions. a) If a solvent molecule acts as a base and
 Unreactive in SN1 reactions because alkenyl and removes one of the β hydrogen atoms, the
phenyl carbocations are relatively unstable and do reaction is E1
not form readily. b) If a solvent molecule reacts as a nucleophile
 Unreactive in SN2 reactions because the carbon– at the positive carbon atom, the reaction is SN1
halogen bond of an alkenyl or phenyl halide is - E1 reactions almost always accompany SN1
stronger than that of an alkyl halide, double bond reactions.
or benzene ring repel the approach of a
nucleophile from the back side.

 In general, SN2 and SN1 can't happen in sp2 and sp How to favor an E2 Mechanism?
 When a synthesis must begin with a primary alkyl
halide, use a bulky base.
XIV. The Elimination Reaction of Alkyl halides Why? Because the steric bulk of the base will inhibit
substitution
 Two possible reaction pathways that an alkyl halide  Use a high concentration of a strong and
1) Substitution Nucleophile attack → nonpolarizable base such as an alkoxide.
substitution Why? Because a weak and polarizable base would not
Backside attack → inversion of drive the reaction toward a bimolecular reaction,
configuration. thereby allowing unimolecular processes (such as SN1
2) Elimination (E) Base removes H → or E1 reactions) to compete.
elimination → alkene formation.  Use elevated temperature because heat generally
Single-step, concerted process. favors elimination over substitution.
 Both occur on the same substrate.
 Which one dominates depends on conditions
 Strong base, high temperature → Elimination XVII. How To Determine Whether
(E2) favored Substitution or Elimination Is Favoured
 Strong nucleophile, low temperature →
Substitution (SN2) favored  Primary Substrates – If the base is strong,
 Bulky base/nucleophile → Elimination (E2) substitution is favored
favored - because the base can easily approach the carbon
 Primary substrate → SN2, Tertiary substrate → bearing the leaving group
E2 or SN1  Secondary Substrate – If the base is strong,
elimination is favorable
XV. Dehydrogenation - steric hindrance in the substrate makes
- Removal of a halogen substitution more difficult
−¿¿
-Conjugate base of alcohols (alkoxide ions, R – O ) is  Tertiary Substrate – Severe steric hindrance,
often used as the base in this reaction. elimination is highly favored, especially at higher
- alpha (α) carbon atom, carbon atom that bears the temperatures
leaving group  High Steric Hindrance = Elimination
- beta (β) carbon atom, any carbon atom adjacent to it  High Temperature = Elimination
- Dehydrohalogenation of alkyl halides, however, can  Bulky base/Nucleophile = Elimination
often yield more than one product.  Strong Basicity, Slightly Polarizable = Elimination
 Weak Basicity, High Polarizability = Substitution
XVI. Elimination

A. Bimolecular Elimination (E2)