Nucleophilic Reactions
Properties and Substitution Reactions of Alkyl halides
John Wilfred T. Malabanan RPh
 Has a halogen atom bonded to an sp3-hybridized
carbon atom
 Carbon-halogen bond in an alkyl halide is polartized
Alkyl Halides
because the halogen is more electronegative than
carbon. Therefore, the carbon atom has a partial
positive charge (∂+) and the halogen has a partial
negative charge (∂-)
 Alkyl halides are classified int primary, secondary and
tertiary
 Aryl halides = aromatic ring
with halogen substituent
 Alkenyl Halide = Halogen
double bonded to a carbon
 Phenyl Halide = aromatic ring
is a benzene
 Alkyl halides are poorly
Physical
Properties of
Alkyl Halide
soluble in water
 Chloroalkanes are
carcinogenic and should be
used under the fumehood.
 Nucleophile (Nu:) displaces a leaving group (LG) in the
molecule that undergoes substitution,
Nucleophilic
Substituion
 Nucleophile = always a Lewis Base (electron Pair
Donor); may be negatively charged or neutral.
 Leaving grou = Lewis Acid ( electron Pair Acceptor)
 Often substrate is an alkyl halide (R-X) and the leaving
group is a halide anion (X)
The nucleophile uses
its electron pair to
form a new covalent
bond
with
the
substrate carbon.
Heterolytic bond cleavage
-happens in the bond
between the substrate and
the leaving group
-the unshared electron pair of
the nucleophile forms a new
bond to the carbon atom.
Lewis
Base
Nu(-) + R-LG ----- R-Nu + LG(-)
The bond between the
carbon and the leaving
group breaks, giving
both electrons from the
bond to the leaving
group.
The leaving leaving
group gains the pair of
electrons
that
originally bonded it in
the substrate.
 Nucleophilic Substitution by a Negatively
Charged Nucleophile Results in a Neutral
product
Solvolysis
-the nucleophile is a solvent
molecule. Since solvent
molecules are present in
great excess the equilibrium
favors the transfer of proto
from the alkyloxonium ion to
a water molecule.
 OH + R-X ------> H-O-R + X(-)
 Nucleophilic Substitution by a Neutral
Nucleophile Results initially in a
positively charged product.
 H-O-H + R-X ----> H2O(+)R + X(-)
 Then it will under go proton transfer and
yield a netral product of H-O-R + H3O(+)
+X(-)
 To act as a substrate the nucleophilic substituition
Leaving group
reaction must have a good leaving group
 A Good Leaving group is a substituent that can leave a
relatively stable, weakly basic molecule or ion
CH3-Cl+OH ---- CH3OH + Cl(-)
Rate of Reaction = (CH3Cl)(OH)
 The reaction is said to be in the
Sn2 Reaction
(substitution,
nucleophilic,
bimolecular)
second over all order.
 OH and CH3Cl must collide.
 Bimolecular reaction – two species
are involved
 Molecularity - the number of
species involved in a reaction step.
• Nucleophile approaches the carbon bearing the leaving
Mechanism of
SN2 Reaction
group form the back side directly opposite the leaving
group
• As the nucleophile froms a bond and the elaving group
departs, the substrate carvon atom undergoes inversion
• SN2 reaction proceeds in a single step (without
intermediates) through an unstable arrangement of atoms
called the transition state.
Free Energy of activation - difference in energy between rge reactants and the transition stage
Free Energy change for the reaction – difference between the reactants and the products
Mechanism for
SN1 Reaction
 It is the nucleophilic substitution in
which the nucleophile is a molecule
of the solvent.
Solvolysis
Reaction
 When the solvent is water we call
the reaction hydrolysis.
 When the solvent is methanol we
call it mathanolysis.
 1. Structure of the substrate
Factors affecting
the relative rates
of SN1 and SN2
reactions.
 Concentration and reactivity of the
nucleophile
 Effect of solvent
 Nature of leaving group
 Steric Effect – an effect of the relative rates caused
by the space-filling properties of those parrs of a
molecule attached at or near the reacting site.
 Steric Hindrance – when the spatial arrangement
Structure of the
substrate
of atoms or groups at or near a reacting site of a
molecule hinders or retards a reaction.
 Hamond-Leffler postulate – the transition-state
structure for an uphill energy step should show a
strong resemblance to the product structure from
that step.
 A negatively charged nucleophile is always a
more reactive nucleophile than its conjugate
acid.
HO (-) > H2O and RO (-) > ROH
Concentration
and Strength
 Ina group of nucleophiles in which the
nucleophilic atom is the same,
nucleophilicities parallel basicities.
RO- > HO- >> RCO2- >ROH > H2O
 When the nucleophilic atoms are different,
nucleophilicities may not parallel basicities.
HS- > N=C- > I- >HO-
 Polar aprotic Solvents – SN2
Solvent Effects
-solubilize cations well using their unshared electron
pairs but do not interact as strongly with anions because
they cannot hydrogen bond with them and because the
positive regions of the solvent are shielded by steric
effects from the anion.
- Acetone, DMSO, DMF, HMPA
 Polar protic Solvents – SN1
-has atleast one hydrogen atom capable of participating
in a hydrogen bond
Solvent Effects
-EtOh, MeOH facilitate the formation of a carbocation by
forming hydrogen bonds with the leaving group as it
departs, thereby lowering the energy of the transition
state leading to a carbocation.
General trend of halide nucleophilicity in polar aprotic
solvents: F > Cl > Br > I
General trend of halide nucleophilicity in polar protic
solvents: I > Br > Cl > F
 Larger atoms has greater polarizabilitym
 A substrate that can form a relatively stable carbocation
 A realtively weak nucleophile
 A polar, protic solvent such as EtOH, MeOH or H2O
Summary of
SN1 reactions
The SN! Mechanism is therefore important in solvolysis
reactions of tertiary alkyl halides, especially when the
solvent is highly polar. In a solvolysis reaction the
nucleophile is weak because it is a neutral molecue rather
than an anion.
 A substrate with a relatively unhindered leaving group
Summary of
SN2 Reaction
 Tertiary halides do not react by SN2 mechanism
 High concentration of the nucleophile
 A polar, aprotic solvent
Synthesis of Alkene:
Elimination reactions
 Most important means for synthesizing alkenes. In
an elimination reaction the fragments of some
molecule are removed (eliminated) from adjacent
atoms of the reactant.
Elimination
reaction
Dehydrohalogenation
Homework: Give a List of Strong Bases used in Dehydrohalogenation
 Widely used method of synthesizing alkenes via
the elimination of HX from adjacent atoms.
 The best reaction conditions to use when
synthesizing an alkene by dehydrohalogenation
are those that promote an E2 mechanism.
Dehydrohalogenation
 In an E2 mechanism, a base removes a b hydrogen
from the b carbon, as the double bond forms and a
leaving group departs from the a carbon.
 Use a secondary or tertiary alkyl halide if
possible.
Why? Because steric hindrance in the substrate will
inhibit substitution.
 When a synthesis must begin with a primary
How To Favor an
E2 Mechanism
alkyl halide, use a bulky base.
Why? Because the steric bulk of the base will
inhibit substitution.
 Use a high concentration of a strong and
nonpolarizable base such as an alkoxide.
Why? Because a weak and polarizable base would
not drive the reaction toward a bimolecular
reaction, thereby allowing unimolecular processes
(such as SN1 or E1 reactions) to compete.
 Sodium ethoxide in ethanol (EtONa/EtOH) and
How To Favor an
E2 Mechanism
potassium tert-butoxide in tert- butyl alcohol (tBuOK/t-BuOH) are bases typically used to promote
E2 reactions
Why? Note that in each case the alkoxide base is
dissolved in its corresponding alcohol. (Potassium
hydroxide dissolved in ethanol or tertbutyl alcohol is
also sometimes used, in which case the active base
includes both the alkoxide and hydroxide species
present at equilibrium.)
 Use elevated temperature because heat
How To Favor an
E2 Mechanism
generally favors elimination over
substitution.
Why? Because elimination reactions are
entropically favored over substitution reactions
 Potassium Hydroxide dissolved in
Bases Used in
Dehydrohalogenation
ethanol (KOH/EtOH) = sometimes
used
 Conjugate bases of Alcohols, such
as sodium ethoxide (EtONa) is more
advantageous.
 The conjugate base of an alcohol (an
alkoxide) can be prepared by treating
an alcohol with an alkali metal.
Bases Used in
Dehydrohalogenation
Alcohol
Sodium Alkoxide
 Oxidation-reduction
 Sodium reacts with Oxygen atoms to
generate Hydrogen gas and the
alkoxide anion.
Sodium alkoxides can also be prepared
by allowing an alcohol to react with NaH.
Bases Used in
Dehydrohalogenation
RO-H + Na:H  R-O-Na+ +H2
Bases Used in
Dehydrohalogenation
Sodium (and potassium) alkoxides are usually
prepared using an excess of the alcohol,
where the excess alcohol becomes the
solvent for the reaction. Sodium ethoxide is
frequently prepared this way using ethanol
Potassium Tert-butoxide (t-BuOK) is another
highly effective base dehydrohalogenation. It
can be made by:
Bases Used in
Dehydrohalogenation
 Formation of the More Substituted Alkene
is Favored with a Small Base.
Zaitsev’s Rule
 Dehydrohalogenation of many alkyl halides, however,
yields more than one product.
 For example, dehydrohalogenation of 2-bromo-2methylbutane can yield two products:
 2-methyl-2-butene and 2-methyl-1-butene, as shown
here by pathways (a) and (b), respectively:
Zaitsev’s Rule
 If we use a small base such as ethoxide or
hydroxide, the major product of the reaction will
be the more highly substituted alkene (which is
also the more stable alkene).
Zaitsev’s Rule
 The reason for this behavior is related to
the double-bond character that develops
in the transition state for each reaction
Zaitsev’s Rule
 Formation of the Less Substituted Alkene
Using a Bulky Base
Zaitsev’s Rule
When an elimination yields the less substituted alkene,
we say that it follows the Hofmann rule.
 The five atoms involved in the transition state of an E2
reaction (including the base) must be coplanar, i.e., lie
in the same plane.
Stereo
Chemistry of E2
Reactions
The anti coplanar conformation is the preferred transition
state geometry
Syn coplanar transition state occurs only with rigid
molecules that are unable to assume the anti arrangement.
Mechanism of E2
Reaction
The E1 Reaction
The E1 Reaction
If a solvent molecule reacts as a nucleophile at the positive carbon
atom of the tert-butyl cation, the product is tert-butyl alcohol or tertbutyl ethyl ether and the reaction is S 1
N
If, however, a solvent molecule acts as a base and removes one of
the b hydrogen atoms, the product is 2-methylpropene and the
reaction is E1
 Most alcohols undergo dehydration
(lose a molecule of water) to form an
alkene when heated with a strong acid.
Dehydration of
Alcohols
1. The temperature and concentration of acid
required to dehydrate an alcohol depend on
the structure of the alcohol substrate.
(a) Primary alcohols are the most difficult to
dehydrate. Dehydration of ethanol, for example,
requires concentrated sulfuric acid and a
temperature of 180 8C:
1. The temperature and concentration of acid
required to dehydrate an alcohol depend on
the structure of the alcohol substrate.
(a) Primary alcohols are the most difficult to
Dehydration of
Alcohols
dehydrate. Dehydration of ethanol, for example,
requires concentrated sulfuric acid and a
temperature of 180 C:
1. The temperature and concentration of acid
required to dehydrate an alcohol depend on
the structure of the alcohol substrate.
Secondary alcohols usually dehydrate under milder
conditions. Cyclohexanol, for example, dehydrates in 85%
phosphoric acid at 165–170 C:
Dehydration of
Alcohols
1. The temperature and concentration of acid
required to dehydrate an alcohol depend on
the structure of the alcohol substrate.
Dehydration of
Alcohols
Tertiary alcohols are usually so easily dehydrated that
relatively mild conditions can be used. tert-Butyl alcohol, for
example, dehydrates in 20% aqueous sulfuric acid at a
temperature of 85 C:
Dehydration of
Alcohols
2. Some primary and secondary alcohols also
undergo rearrangements of their carbon
skeletons during dehydration.
Such a rearrangement occurs in the dehydration of
3,3-dimethyl-2-butanol:
Dehydration of
Alcohols
2. Some primary and secondary alcohols also
undergo rearrangements of their carbon
skeletons during dehydration.
Such a rearrangement occurs in the dehydration of
3,3-dimethyl-2-butanol:
Dehydration of
Alcohols
Dehydration of
Alcohols
Addition of
Halogens to
alkenes
Addition of
Hypophalous
Acids to Alkenes:
Halohydrin
Formation
Addition of
Hypophalous
Acids to Alkenes:
Halohydrin
Formation
Addition of Water
to Alkenes:
Oxymerucration
Addition of Water
to Alkenes:
Oxymerucration
Addition of Water
to Alkenes:
Hydroboration
Addition of Water
to Alkenes:
Hydroboration
Addition of
Carbenes:
Cyclopropene
Synthesis
Addition of
Carbenes:
Cyclopropene
Synthesis
Addition of
Carbenes:
Cyclopropene
Synthesis
Addition of
Carbenes:
Cyclopropene
Synthesis
Simmons-Smith Reaction:
Addition of
Carbenes:
Cyclopropene
Synthesis
Reduction of
Alkenes:
Hydrogenation
Platinum is usually used as PtO2 or Adam’s Catalyst
Reduction of
Alkenes:
Hydrogenation
Platinum is usually used as PtO2 or Adam’s Catalyst
Reduction of
Alkenes:
Hydrogenation
Reduction of
Alkenes:
Hydrogenation
Oxidation of
Alkenes
:Epoxidation and
Hydroxylation
Epoxide = Oxirane
-a cyclic ether with an oxygen atom in a three membered ring.
Oxidation of
Alkenes
:Epoxidation and
Hydroxylation
Oxidation of
Alkenes
:Epoxidation and
Hydroxylation
Oxidation of
Alkenes: Cleavage
to Carbonyl
Compounds