Ch 6- Alkyl Halides
Structures and Properties
• Halogen is connected to a tetrahedral carbon
• The carbon-halogen bond is polarized with the
carbon having a partial positive charge and
the halogen having a partial negative charge
• The size of the halogen increases as you move
down the group
• Consequently, the C-X bond lengths increase
so the bond strength decreases
Structures and Properties
• Compounds with a halogen bonded to an sp2
carbon are called vinylic halides or phenyl
halides
• Ex.
• Alkyl and aryl halides have very low solubility
in water, but very stable in each other
Nucleophilic Substitution Reactions
• General Reaction:
• Examples:
• Nucleophile- a species with an unshared
electron pair.
– Usually has either a full or partial negative charge
– It is electron rich
Nucleophilic Substitution Reactions
• The nucleophile reacts with the alkyl halide,
replacing the halogen substituent
• A substitution reaction takes place and the
halogen substituent, called the leaving group,
departs as an ion
• Because the substitution is initiated by a
nucleophile, it is called a nucleophilic
substitution reaction
Nucleophilic Substitution Reactions
• In the reaction, the C-X bond undergoes heterolysis
and the electron pair from the nucleophile is used
to make a new bond
• There are two ways this can happen:
1) The C-X bond can break then the Nu-C bond forms
2) Bond making and breaking can happen at the same
time.
Nucleophilic Substitution Reactions
• When deciding which of these will occur, the
decision will depend primarily on the
structure of the alkyl halide.
Nucleophiles
• A nucleophile is a reagent that seeks a positive
center
• Here, the positive center is the carbon bonded to
the halogen which has a partial positive charge
• A nucleophile is any negative ion or any neutral
molecule that has at least one unshared pair of
electrons
• Ex.
Leaving Groups
• To act as a substrate, in a nucleophilic
substitution reaction, a molecule must have a
good leaving group
• A good leaving group is a substituent that can
leave as a relatively stable, weakly basic
molecule or anion.
• Recall that halogen ions are very weak bases
because hydrogen halides are very strong acids
Kinetics of a Nucleophilic Substitution
Reaction: An Sn2 reaction
• To understand how the rate of a reaction is
measured, we will consider the following reaction:
60oC
H3C
Cl
+ OH
H2O
H3C
OH
+
Cl
• Reaction Rates are temperature dependant so we
have to discuss the reaction at a specific
temperature
Kinetics of a Nucleophilic Substitution
Reaction: An Sn2 reaction
• The rate of the reaction can be determined
experimentally by measuring the rate at which
chloromethane or hydroxide disappear or the
rate that methanol or chloride ion appears
• We do this by taking a small sample of the
reaction mixture at different times and
measure the concentration of chloromethane,
hydroxide, methanol, or chloride.
Kinetics of a Nucleophilic Substitution
Reaction: An Sn2 reaction
• We know the initial concentration of the
reactants because we measured them before
starting the reaction.
Experiment
#
Initial
[CH3OH]
Initial [OH]
Initial Rate
1
.0010
1.0
4.9x10-7
2
.0020
1.0
9.8x10-7
3
.0010
2.0
9.8x10-7
4
.0020
2.0
19.6x10-7
Kinetics of a Nucleophilic Substitution
Reaction: An Sn2 reaction
• Notice the rate depends on both the
concentration of chloromethane and
hydroxide
• When we double one, the rate doubled
• When we doubled both the rate goes up by a
factor of 4!
• We can express this by a proportionality:
𝑅𝑎𝑡𝑒 ∝ [𝐶𝐻3 Cl] [OH]
Kinetics of a Nucleophilic Substitution
Reaction: An Sn2 reaction
• This proportionality can be expressed as an
equation by including a proportionality constant (k)
called the rate constant:
Rate = k [CH3Cl] [OH]
• For this reaction at this temperature, the rate
constant equals 4.9x10-4 L/mol sec
• This reaction is said to be second order overall
• In order for the reaction to take place, a hydroxide
ion and a chloromethane molecule must collide
Kinetics of a Nucleophilic Substitution
Reaction: An Sn2 reaction
• Therefore, the reaction is bimolecular, which
means 2 molecules are involved in the rate
determining step
• We call this kind of reaction an Sn2 reaction,
Substitution, nucleophilic, Bimolecular
Mechanism for the Sn2 reaction
• The negative hydroxide approaches the partially
positive carbon from the backside
• Concerted Reaction- bond breaking and bond
making happen at the same time.
• Configuration of the carbon being attacked is
inverted due to the backside attact.
Stereochemistry of Sn2 reaction
• The nucleophile approaches from the backside,
from the side directly opposite the leaving group
• This causes a change in configuration
• The carbon being attacked inverts like an umbrella
• Ex.
• Inversion also always takes place with acyclic
stereogenic carbons
Reaction of t-butyl chloride with OH:
Sn1 reaction
• When t-butyl chloride reacts with hydroxide in
water/acetone, the kinetic results are very
different than with Sn2 reactions
• The rate of formation of t-butyl alcohol is
dependent on the concentration of t-butyl
chloride, but it is independent of the
concentration of hydroxide.
• Doubling the t-butyl chloride doubles the rate
• But changing [OH] has no effect
Reaction of t-butyl chloride with OH:
Sn1 reaction
• The t-butyl chloride reacts by substitution at
virtually the same rate in pure water ([OH]=10-7 M)
as it does in 0.05M aqueous sodium hydroxide!
• Thus the rate for this substitution is first order with
respect to t-butyl chloride and first order overall
• From this we can conclude that the hydroxide does
not participate in the transition state of the step
that controls the rate of the reaction.
• Only the t-butyl chloride does
Reaction of t-butyl chloride with OH:
Sn1 reaction
• The reaction is said to be unimolecular in the
rate determining step
• It is an example of an Sn1 reaction.
Substitution, nucleophilic, Unimolecular
• Because only the t-butyl chloride is present in
the rate determining transition state, we can
conclude that the reaction must have multiple
steps
Multistep Reactions and the Rate
Determining Step, RDS
• If a reaction takes place in a series of steps,
and one of the steps is slower than all the
others, the rate of the overall reaction will
essentially be the same as that slow step
• That slow step is called the Rate-Determining
Step, (RDS).
Mechanism for Sn1
• The mechanism has two intermediates
Carbocations
• Carbocations are trigonal planar
• The carbon bearing the positive charge is sp2
hybridized
• The carbon is electron deficient as it only has
6 electrons.
• Overall stability:
Stereochemistry of Sn1
• Because the carbocation formed in the first
step is planar, the nucleophile can attach from
either side.
• Often, this has no effect because the same
product is formed
• However, if the starting reactant is optically
active, this will always result in a racemization
• Racemization- a reaction transforms an
optically active compound into a racemic form
Stereochemistry of Sn1
• Racemization takes place whenever the reaction
causes chiral molecules to be converted to an
achiral intermediate
• Ex
• The Sn1 reaction proceeds through the
carbocation, which because it is trigonal planar, is
achiral. The nucleophile can attack the
carbocation from either side, thus producing both
enantiomers in equal amounts.
Solvolysis
• The Sn1 reaction of an alkyl halide with water is an
example of solvolysis.
• Solvolysis reaction- a nucleophile substitution in
which the nucleophile is a molecule of the solvent
• The previous reaction was in water, so it is also
called a hydrolysis
• If the reaction was in methanol, it would be a
methanolysis.
• Examples:
Factors affecting the rates of Sn1 and
Sn2 reactions
• Now we know the mechanism Sn1 and Sn2
• The next thing is too explain why
chloromethane went Sn2 t-butylchloride went
Sn1
• By the time we are done, you will be able to
predict which pathway a reaction will undergo
Choosing between Sn2 and Sn1
• If a given alkyl halide and nucleophile react
rapidly via Sn2 but slow by Sn1 then a Sn2
pathway will be followed by most of the
molecules and vice versa
• A number of factors affect the relative rates of
Sn1 and Sn2 reactions:
Factors that affect rates of Sn1 and Sn2
The most important are:
1) Structure of the substrate
- Is it a primary, secondary, tertiery alkyl halide?
2) The concentration and reactivity of the nucleophile
- For bimolecular reactions only
3) The effect of the solvent
4) The nature of the leaving group
Effect of the Structure of the Substrate
• In Sn2 reactions, simple alkyl halides have the
following general order of reactivity
• The important factor behind this order is a steric
effect
• Steric Effect- an effect on relative rates caused by
the space-filling properties of those parts of a
molecule attached at or near the reaction site
Steric Effect
• One type of steric effect is Steric Hindrance
• Steric Hindrance- the spatial arrangement of
the atoms or groups at or near the reacting
site of a molecule hinders or retards a reaction
Effect of the Structure of the Substrate
• In Sn1 reactions, the primary factor that
determines the reactivity of a substrate is the
relative stability of the carbocation that is
formed.
• Because of this, only the tertiary alkyl halides
react via Sn1 with reasonable rates
• There are exceptions to this that we will cover
later
Effect of Concentration and Strength
of the Nucleophile
• In Sn1 reaction, the nucleophile does not
participate in the RDS, so the concentration and
strength does not matter
• In Sn2, the rate is dependent on both the substrate
and the nucleophile
• We have already seen how doubling the
concentration of the nucleophile doubles the rate
• We identify good and bad nucleophiles based on
their rate of reaction in similar situations
• Ex
Nucleophile Strength vs Structure
• The relative strengths of nucleophiles can be
correlated with two structural features:
1) A negative charged nucleophile is always a
more reactive nucleophile than its conjugate
acid
2) In a group of nucleophiles in which the
nucleophilic atom is the same,
nucleophilicities parrallel basicities.
Solvent effects on Sn2 Reactions
• Protic Solvents- those having a Hydrogen
bond to an electronegative element such as
Oxygen
• These solvents can hydrogen bond to the
nucleophile and hinder its reaction in an Sn2
reaction
• Hydrogen bonding effects decreases with
anion size
Solvent effects on Sn2 Reactions
• Nucleophilicity of halide anions in protic
solvents:
• Relative Nucleophilicity in Protic Solvents:
Solvent effects on Sn2 Reactions
• Aprotic Solvents- Solvents whose molecules
do not have a hydrogen that is attached to an
electronegative atom.
• Aprotic Solvents are especially useful for Sn2
reactions!
• Examples of Aprotic solvents:
Solvent effects on Sn2 Reactions
• Aprotic Solvents dissolve ionic compounds
and solvate cations well but not anions
because their positive centers are well
shielded.
• Because anions are not solvated, small anions
react faster.
• Nucleophilicity in Aprotic Solvents:
Solvent effects on Sn2 Reactions
• The rates of Sn2 reactions are vastly increased
when they are carried out in polar aprotic
solvents!
• Take Home: Aprotic Solvents= Sn2
Solvent effects on Sn1 Reactions
• Polar protic solvents greatly increase the rate
of ionization of alkyl halides
• This is the RDS, therefore it increases the rate
of the Sn1 reactions.
• So, in most cases, use of a protic solvent = Sn1
Nature of Leaving Group
• The more stable an anion, the better the leaving
group
• General order of stabilities:
• Some “Super” leaving groups are shown on page
269
• Also, in some cases, bad leaving groups can be
converted into good leaving groups with simple
acid/base chemistry
Summary of Sn1 vs Sn2
• Reactions of alkyl halides by Sn1 are favored by:
– Substrates that form stable carbocations
– Use of weak nucleophiles
– Use of polar protic solvents
• Sn2 favored by:
– Unhindered alkyl halide
– Strong nucleophiles
– Aprotic solvents
– High concentrations of nucleophile
Final Notes on Sn2/Sn1
• Note the chart on page 272
• These are all the functional group transformations
possible through Sn2/Sn1 reactions!
• Remember, Sn2 reactions always proceed with
inversion of the stereocenter while Sn1 reactions
proceed with the total loss of stereocenter and
result in racemic mixture
• Watch for “Double Inversion”
Elimination Reations
• Elimination reactions are important reactions
of alkyl halides that compete with Sn2/Sn1
reactions
• Recall, in elimination reactions, 1 thing is
eliminated from each of two adjacent carbons
to form a double bond
• Ex.
Elimination Reactions
• A widely used method is the elimination of HX
from an Alkyl Halide
• Ex
• When the elements of a hydrogen halide are
eliminated from a haloalkane, the reaction is
called a dehydrohalogenation.
Elimination Reactions
• In these eliminations, as in Sn1/Sn2, there is a
Leaving group and an attacking Lewis base
that posses an electron pair
• They are also called β-elimination since the
hydrogen that is removed is from the beta
carbon
Base Used in Dehydrohalogenations
• Very strong bases are used for elimination reactions
• Typically, the sodium or potassium salts of alcohols
are used
• These sometimes present problems because they
can also react as nucleophile
• To avoid this, the salt of t-butanol is used
• t-butoxide is very bulky which prevents it from
being a good nucleophile
Mechanisms for Elimination Reactions
• Just like substitutions, there are two
• One has a bimolecular T.S. = E2
• One has an unimolecular T.S. = E1
• Mechanism for E2
Mechanisms for Elimination Reactions
• Mechanism for E1
• Problem!! E1 and Sn1 usually complete to give
mixed products
Substitution vs Elimination
• All nucleophiles are potential bases and vice
versa
• So substitution and elimination compete
• Sn2 vs E2
– Both favored by high concentration of
nucleophile/base
Sn2 vs E2
• 1o LG
– With a 1o alkyl halide and unhindered base favors
substitution
– With a hindered base, elimination is favored
• 2o LG
– Strong base favors elimination due to steric hinderance
• 3o LG
– No chance for Sn2 only elimination
Effect of Temperature
• Increasing the temperature favors
• Low temperature favors substitution
Sn1 vs E1
• E1 favored by:
– Stable cations
– Poor nucleophiles
– Use protic solvents
– High temperatures
• Sn1- very hard to favor
– Use low temperatures
– Strong nucleophiles
– Aprotic solvents
Overall Summary