Transcript Alkyl halide

Chapter 10
Alkyl Halides: Nucleophilic
Substitutions and Eliminations
© 2006 Thomson Higher Education
Alkyl Halides
Alkyl halide or haloalkanes
• Compounds with a halogen atom bonded to a saturated
sp3-hybridized carbon atom
• Widespread in nature
•
•
Chloromethane is released in large amounts by ocean kelp,
as well as by forest fires and volcanoes
Vast array of industrial applications
•
Use as inhaled anesthetics, refrigerants, pesticides, and
solvents
Alkyl Halides
Other halo-substituted compounds are providing important
leads to new medicines
•
The compound epibatidine has been isolated from the skin of
Ecuadorian frogs and found to be more than 200 times as
potent as morphine at blocking pain in animals
Alkyl Halides
Alkyl halides are not often involved in the
biochemical pathways of terrestrial organisms
• The kinds of reactions they undergo –
nucleophilic substitutions and eliminations –
are frequently involved
• Alkyl halide chemistry acts as a relatively
simple model for many mechanistically similar
but structurally more complex reactions found
in biomolecules
10.1 Naming Alkyl Halides
Haloalkanes
•
•
Commonly called alkyl halides
The halogen is treated as a substituent on a parent
alkane chain
Alkyl halides can be named by following three steps
1. Find the longest chain, and name it as the
parent
•
If a double or triple bond is present, it must be included
in the parent chain
Naming Alkyl Halides
Number the carbons of the parent chain beginning at
the end nearer the first substituent, whether alkyl or
halo
2.
•
3.
Assign each substituent a number according to its position
on the chain
If the parent chain can be properly numbered from
either end by step 2, begin at the end nearer the
substituent that has alphabetical precedence
Naming Alkyl Halides
Many simple alkyl halides are also named by identifying
first the alkyl group and then the halogen
• CH3I can either be called iodomethane or methyl
iodide
• Such names will not be used in this textbook
10.2 Preparing Alkyl Halides
Methods of preparing alkyl halides
• Reactions of HX and X2 with alkenes in electrophilic
addition reactions
•
•
The hydrogen halides HCl, HBr, and HI react with
alkenes by a polar mechanism to give the product of
Markovnikov addition
Bromine and chlorine undergo anti addition through a
halonium ion intermediate to give 1,2-dihalogenated
products
Preparing Alkyl Halides
Preparing alkyl halides from alcohols
• Many common methods have been developed to transform
alcohols into alkyl halides
• Treat the alcohol with HCl, HBr, or HI
•
•
•
Simplest method
The reaction works best with tertiary alcohols, R3COH
Primary and secondary alcohols react slowly and at
higher reaction temperatures
Preparing Alkyl Halides
The reaction of HX with a tertiary alcohol is so rapid that
it is often carried our simply by bubbling the pure HCl
or HBr gas into a cold ether solution of the alcohol
•
Conversion of 1-methylcyclohexanol into 1-chloro-1methylcyclohexane
Preparing Alkyl Halides
Primary and secondary alcohols are best converted into
alkyl halides by treatment with either thionyl chloride
(SOCl2) or phosphorus tribromide (PBr3)
•
Reactions normally take place readily under mild
conditions
• Reactions are less acidic and less likely to cause acidcatalyzed rearrangements than the HX method
10.3 Reactions of Alkyl Halides:
Grignard Reagents
Grignard Reagents:
•
•
•
•
Named after discoverer, Victor Grignard
Alkylmagnesium halide, RMgX, produced from reaction of alkyl
halides, RX, with magnesium metal in ether or tetrahydrofuran
(THF) solvent
Examples of organometallic compounds because they contain a
carbon-metal bond
They can also be made from alkenyl (vinylic) and aryl (aromatic)
halide
Halogens
Reactions of Alkyl Halides:
Grignard Reagents
The carbon-magnesium bond within the Grignard
reagent is polarized
• The carbon atom is both nucleophilic and basic
Reactions of Alkyl Halides:
Grignard Reagents
Grignard Reagents are magnesium salts, R3C- +MgX, of
a carbon acid, R3C-H
•
They react with weak acids such as H2O, ROH, RCO2H,
and RNH2 to abstract a proton and yield hydrocarbons
•
Since hydrocarbons are weak acids, with pKa’s in the range
of 44 to 60, carbon anions are very strong bases
Organic halide
•
•
Grignard Reagent
Hydrocarbon
They have no role in biochemistry
They are useful carbon-based nucleophiles in many
laboratory reactions
• They act as models for more complex carbon-based
nucleophiles that are important in biological chemistry
10.4 Discovery of the Nucleophilic
Substitution Reaction
In 1896, the German chemist Paul Walden found that the pure
enantiomers (+) and (-)-malic acids, could be interconverted
by a series of simple substitution reactions
•
Walden’s cycle of
reactions
interconverting (+) and
(-)-malic acids
• Because (-)-malic
acid was converted
into (+)-malic acid,
some reactions in
the cycle must have
occurred with a
change, or
inversion, in
configuration at the
chirality center
Discovery of the Nucleophilic
Substitution Reaction
Nucleophilic substitution reactions
• One of the most common and versatile reaction
types in organic chemistry
• Explain the transformations taking place in Walden’s
cycle
• Each step involves the substitution of one
nucleophile (chloride ion, Cl-, or hydroxide ion, HO-)
by another
Discovery of the Nucleophilic
Substitution Reaction
•
Series of investigations undertaken
during the 1920s and 1930s to
clarify the mechanism of
nucleophilic substitution reactions
and to find out how inversions of
configuration occur
• Three-step sequence
interconverts two enantiomers
of 1-pheylpropan-2-ol
• At least one step must
involve inversion of
configuration of chirality
center
• Chirality centers are
marked by asterisks
• Bonds broken in each
reaction are indicated by
red wavy lines
Discovery of the Nucleophilic
Substitution Reaction
Nucleophilic substitution reaction of a primary or
secondary alkyl halide or tosylate always proceeds
with inversion of configuration
• The inversion of stereochemical configuration must
take place in the second step, the nucleophilic
substitution of tosylate ion by acetate
Worked Example 10.1
Predicting the Stereochemistry of a Nucleophilic
Substitution Reaction
What product would you expect from a nucleophilic
substitution reaction of (R)-1-bromo-1-phenylethane
with cyanide ion, -C≡N as nucleophile? Show the
stereochemistry of both reactant and product,
assuming that inversion of configuration occurs.
Worked Example 10.1
Predicting the Stereochemistry of a Nucleophilic
Substitution Reaction
Strategy
• Draw the R enantiomer of the reactant and
then change the configuration of the chirality
center while replacing the –Br with a -CN
Worked Example 10.1
Predicting the Stereochemistry of a Nucleophilic
Substitution Reaction
Solution
10.5 The SN2 Reaction
Kinetics
•
•
Study of reaction rates
The direct relationship between the rate at which the reaction
occur and the concentrations of the reactants found in every
chemical reaction
• Kinetics of a simple nucleophilic substitution:
•
•
•
At a given temperature and concentration of reactants, the
substitution occurs at a certain rate
If concentration of OH- doubles, the frequency of encounter
between the reaction partners double and the reaction rate
also doubles
If concentration of CH3Br doubles, the reaction rate again
doubles
The SN2 Reaction
Second-order reaction
• A reaction in which the rate is linearly dependent on
the concentrations of two species
• Mathematically expressed using the rate equation
Reaction rate = Rate of disappearance of reactant
= k × RX  ×  - OH 
where
 RX  = CH Br concentration in molarity
3
 - OH  = -OH concentration in molarity
k = A constant value (the rate constant)
The SN2 Reaction
SN2 reaction
• Short for substitution, nucleophilic, bimolecular
• A mechanism that accounts for both the inversion of
configuration and the second-order kinetics that are
observed with nucleophilic substitution reactions
• Suggested in 1937 by E. D. Hughes and Christopher
Ingold
• Essential features of the SN2 Reaction
•
•
Takes place in a single step without intermediates
Incoming nucleophile reacts with the alkyl halide or
tosylate (the substrate) from a direction opposite the
group that is displaced (the leaving group)
The SN2 Reaction
The mechanism of the SN2 reaction when
(S)-2-bromobutane reacts with –OH to
give (R)-butan-2-ol
• The reaction takes place in a single step
• Incoming nucleophile approaches from a
direction 180º away from the leaving
halide ion, thereby inverting the
stereochemistry at carbon
The SN2 Reaction
•
The SN2 reaction
occurs when an
electron pair on
the nucleophile
Nu:- forces out the
group X:-, which
takes with it the
electron pair from
the former C-X
bond
• The transition
state of an SN2
reaction has a
planar
arrangement of
the carbon
atom and the
remaining
three groups
10.6 Characteristics of the SN2
Reaction
Rate of a chemical reaction is determined by ∆G‡, the energy
difference between reactant ground state and transition state
•
Lowering the reactant
energy or raising the
transition-state energy
increases ∆G‡ and
decreases the reaction rate
•
Raising the reactant energy
or decreasing the transitionstate energy decreases ∆G‡
and increases the reaction
rate
Characteristics of the SN2
Reaction
The Substrate: Steric Effects in the SN2 Reaction
• A bulky substrate prevents the easy approach of the
nucleophile, making bond formation difficult
•
The transition state for reaction of a sterically hindered
substrate is higher in energy and forms more slowly
than the corresponding transition state for a less
hindered substrate
Bromomethane is
readily accessible,
resulting in a fast SN2
reaction
Characteristics of the SN2
Reaction
Steric hindrance to the SN2 reaction. The carbon atom in (a)
is readily accessible, resulting in a fast SN2 reaction. The
carbon atoms in (b) bromoethane (primary), (c) 2bromopropane (secondary), and (d) 2-bromo-2methylpropane (tertiary) are successively more hindered,
resulting in successively slower SN2 reactions
Characteristics of the SN2
Reaction
SN2 reactions occur only at relatively unhindered sites
• Relative reactivities for some different substrates are
as follows:
Characteristics of the SN2
Reaction
• Vinylic halides (R2C=CRX) and aryl halides are
unreactive toward SN2 reaction
•
The incoming nucleophile would have to approach in
the plane of the carbon-carbon double bond to carry
out a backside displacement
Characteristics of the SN2
Reaction
The Nucleophile
• A Lewis base
• Any species either neutral or negatively charged that has
an unshared pair of electrons
• If negatively charged, the product is neutral
•
If neutral, the product is positively charged
Characteristics of the SN2
Reaction
Wide array of substances prepared using SN2 reactions
Characteristics of the SN2
Reaction
Trends found in SN2 reactions:
• Nucleophilicity roughly parallels basicity when
comparing nucleophiles that have the same reacting
atom
•
•
•
OH- is more basic and more nucleophilic than acetate
ion, CH3CO2-, which in turn is more basic and more
nucleophilic than H2O
“Nucleophilicity” is the affinity of a Lewis base for a
carbon atom in the SN2 reaction
“Basicity” is the affinity of a base for a proton
Characteristics of the SN2
Reaction
•
Nucleophilicity usually increases going down a
column of the periodic table
•
HS- is more nucleophilic than HO-
•
Halide reactivity order is I-> Br-> Cl-
•
•
Going down the periodic table, elements have their valence
electrons in successively larger shells, where they are
successively farther from the nucleus, less tightly held, and
consequently more reactive
Negatively charged nucleophiles are usually more
reactive than neutral ones
•
SN2 reactions are often carried out under basic conditions
rather than neutral or acidic conditions
Characteristics of the SN2
Reaction
The Leaving Group
• Best leaving groups are those that best stabilize the
negative charge in the transition state
•
•
The greater the extent of the charge stabilization by the
leaving group, the lower the energy of the transition
state and the more rapid the reaction
Weak bases such as Cl– and tosylate ion make good
leaving groups, while strong bases such as OH– and
NH2– make poor leaving groups
Characteristics of the SN2
Reaction
Alkyl fluorides, alcohols, ethers, and amines do not
typically undergo SN2 reactions
•
To carry out an SN2 reaction with an alcohol, the HO– must
be converted into a better leaving group
•
•
A primary or secondary alcohol is converted into an alkyl
chloride by reaction with SOCl2
A primary or secondary alcohol is converted into an alkyl
bromide by reaction with PBr3
Characteristics of the SN2
Reaction
Epoxides
• Three-membered cyclic ethers
• Much more reactive than other ethers because of
angle strain in the three-membered ring
•
•
React with aqueous acid to give 1,2-diols
React readily with many other nucleophiles
•
Propene oxide reacts with HCl to give 1-chloropropan-2-ol
by SN2 backside attack on the less hindered primary
carbon atom
Characteristics of the SN2
Reaction
The Solvent
•
Protic solvents – those that contain an –OH or –NH group
– are generally the worst for SN2 reactions
• Decrease the rates of SN2 reactions by lowering the
ground-state energy of the nucleophile
• Methanol and ethanol slow down SN2 reactions by
solvation of the reactant nucleophile
•
Solvent molecules hydrogen bond to the nucleophile and
form “a cage” around it
Characteristics of the SN2
Reaction
•
Polar aprotic solvents, which are polar but do not have –OH or
–NH group, are the best solvents for SN2 reactions
•
•
•
Increase the rates of SN2 reactions by raising the ground-state
energy of the nucleophile
Solvents can dissolve many salts because of their high polarity,
but they solvate metal cations rather than nucleophilic anions
• Bare unsolvated anions have greater nucleophilicity and SN2
reactions take place at correspondingly faster rates
Reaction of azide ion with 1-bromobutane
Characteristics of the SN2
Reaction
A Summary of SN2 Reaction Characteristics
Substrate
Steric hindrance raises the energy of the SN2
transition state, increasing ∆G‡ and decreasing
the reaction rate. As a result, SN2 reactions are
best for methyl and primary substrates
Characteristics of the SN2
Reaction
Nucleophile
Basic, negatively charged nucleophiles are less
stable and have a higher ground-state energy
than neutral ones, decreasing ∆G‡ and
increasing SN2 reaction rate
Characteristics of the SN2
Reaction
Leaving group Good leaving groups (more stable anions)
lower the energy of the transition state
decreasing ∆G‡ and increasing SN2
reaction rate
Characteristics of the SN2
Reaction
Solvent
Protic solvents solvate the nucleophile, thereby
lowering its ground-state energy, increasing ∆G‡,
and decreasing SN2 reaction rate
Polar aprotic solvents surround the accompanying
cation but not the nucleophilic anion, thereby raising
the ground-state energy of the nucleophile,
decreasing ∆G‡ and increasing SN2 reaction rate
10.7 The SN1 Reaction
SN1 reaction
• Unimolecular nucleophilic substitution reaction
The SN1 Reaction
• Rate of reaction depends only on the alkyl halide
concentration and is independent of the H2O
concentration
•
Reaction is a First-order process
•
The concentration of the nucleophile does not
appear in the rate equation
Reacton rate = Rate of disappearance of alkyl halide
= k  RX 
• Rate-limiting step or rate-determining step
• Slowest step of a multi-step chemical reaction
The SN1 Reaction
•
Mechanism of the
SN1 reaction of 2bromo-2methylpropane with
H2O involves three
steps
•
The first step –
spontaneous,
unimolecular
dissociation of
the alkyl bromide
to yield a
carbocation – is
rate-limiting
The SN1 Reaction
SN1 reaction
•
Slower, ratelimiting step
is a
spontaneous
dissociation
of the alkyl
halide to give
carbocation
intermediate
The SN1 Reaction
•
•
If an SN1 reaction is carried out on one enantiomer of a chiral
reactant and proceeds through an achiral carbocation
intermediate, the product will be optically inactive
The symmetrical intermediate carbocation can react with a
nucleophile equally well from either side, leading to a racemic
50 : 50 mixture of enantiomers
The SN1 Reaction
• SN1 reactions on enantiomerically pure substrates do
not occur with complete racemization
•
Most give minor (0-20%) excess if inversion
• Reaction of (R)-6-chloro-2,6-dimethyloctane with H2O
The SN1 Reaction
Ion pairs in an SN1 reaction
•
The leaving group shields one side of the carbocation
intermediate from reaction with the nucleophile, thereby
leading to some inversion of configuration rather than
complete racemization
10.8 Characteristics of the SN1
Reaction
SN1 Reaction
•
Factors that lower ∆G‡ , either by lowering the energy
level of the transition state or by raising the energy level of
the ground state, favor faster SN1 reaction
The Substrate
•
The more stable the carbocation intermediate, the faster
the SN1 reaction
• According to the Hammond postulate any factor that
stabilizes a high-energy intermediate also stabilizes
•
•
the transition state leading to that intermediate
Stability of carbocations 3º > 2 º > 1º > –CH3
Reaction is favored for more highly stabilized
carbocation intermediates
Characteristics of the SN1
Reaction
The resonance-stabilized allylic and benzylic cations
also favor reaction
Characteristics of the SN1
Reaction
Due to resonance stabilization:
• Primary allylic and primary benzylic carbocations are
about as stable as secondary alkyl carbocations
• Secondary allylic and secondary benzylic
carbocations are about as stable as a tertiary alkyl
carbocations
Characteristics of the SN1
Reaction
Allylic and benzylic substrates are particularly reactive
in SN2 and SN1 reactions
•
Allylic and benzylic C-X bonds are about 50 kJ/mol (12
kcal/mol) weaker than the corresponding saturated bonds
Characteristics of the SN1
Reaction
The Leaving group
• An identical reactivity order is found for the SN1
reaction as for the SN2 reaction
Characteristics of the SN1
Reaction
For SN1 reactions
carried out under
acidic conditions
neutral water is
sometimes the
leaving group
•
Mechanism of the
SN1 reaction of a
tertiary alcohol
with HBr to yield
an alkyl halide
•
Leaving group is
neutral water
Characteristics of the SN1
Reaction
The Nucleophile
• Does not affect the SN1 reaction rate
• SN1 reaction occurs through a rate-limiting step in
which nucleophile has no part
Characteristics of the SN1
Reaction
The Solvent
• Solvent effects in the SN1 reaction are due largely to
stabilization or destabilization of the transition state
• Any factor stabilizing the intermediate carbocation
should increase the rate of an SN1 reaction
(Hammond postulate)
•
Carbocation solvation
•
The electron-rich
oxygen atoms of
solvent molecules
orient around the
positively charged
carbocation and
thereby stabilize it
Characteristics of the SN1
Reaction
SN1 reactions take place much more rapidly in polar
solvents such as water and methanol than in
nonpolar solvents such as ether and chloroform
Characteristics of the SN1
Reaction
A Summary of SN1 Reaction Characteristics
Substrates
The best substrates yield the most stable
carbocations. As a result, SN1 reactions
are best for tertiary, allylic, and benzylic,
halides
Leaving group Good leaving groups increase the reaction
rate by lowering the energy level of the
transition state for carbocation formation
Nucleophile
The nucleophile does not affect the reaction rate
Solvent
Polar solvents stabilize the carbocation
intermediate by solvation, thereby increasing the
reaction rate
Worked Example 10.2
Predicting the Mechanism of a Nucleophilic
Substitution Reaction
Predict whether each of the following substitution
reactions is likely to be SN1 or SN2:
Worked Example 10.2
Predicting the Mechanism of a Nucleophilic
Substitution Reaction
Strategy
• Look at the substrate, leaving group, nucleophile,
and solvent
• Decide form the summaries at the ends of
Sections 10.6 and 10.8 whether an SN1 or an
SN2 reaction is favored
•
•
SN1 reactions are favored by tertiary, allylic, or
benzylic substrates, by good leaving groups, by
nonbasic nucleophiles, and by protic solvents
SN2 reaction are favored by primary substrates,
by good leaving groups, by good nucleophiles,
and by polar aprotic solvents
Worked Example 10.2
Predicting the Mechanism of a Nucleophilic
Substitution Reaction
Solution
(a) This is likely to be an SN1 reaction because the
substrate is secondary and benzylic, the
nucleophile is weakly basic, and the solvent is
protic
(b) The is likely to be an SN2 reaction because the
substrate is primary, the nucleophile is a
reasonably good one, and the solvent is polar
aprotic
10.9 Biological Substitution Reactions
SN1 and SN2 reactions are known in biological chemistry
• Pathways for biosynthesis of the many thousands of terpenes
• The substrate in a
biological substitution
reaction is often an
organo diphosphate
rather than an alkyl
halide
•
•
The leaving group
is the diphosphate
ion, PPi, rather than
a halide ion
Diphosphate group
is the “biological
equivalent” of a
halogen
Biological Substitution Reactions
•
Geraniol
Biosynthesis
•
•
A fragrant
alcohol found
in roses and
used in
perfumery
Two SN1
reactions
occur, both
with
diphosphate
ion as the
leaving group
Biological Substitution Reactions
SN2 reactions are involved in almost all biological
methylations, which transfer a –CH3 group from an
electrophilic donor to a nucleophile
• –CH3 donor is S-adenosylmethionine (SAM)
• Contains a positively charged sulfur (a sulfonium ion)
• Leaving group is the neutral S-adenosylhomocysteine
molecule
• In the biosynthesis of epinephrine (adrenaline) from
norepinephrine, the nucleophilic nitrogen atom of
norepinephrine attacks the electrophilic methyl carbon
atom of S-adenosylmethionine, displacing
S-adenosylhomocysteine
•
S-adenosylmethionine is a biological equivalent of CH3Cl
Biological Substitution Reactions
Biosynthesis of epinephrine from norepinephrin
•
Occurs by an SN2 reaction with S-adenosylmethionine
10.10 Elimination Reaction: Zaitsev’s
Rule
When a nucleophile/Lewis base reacts with an alkyl
halide two kinds of reactions can occur
• Substitution where a nucleophile can react at carbon
to substitute for the halide
• Elimination where a nucleophile can react at a
neighboring hydrogen to cause elimination of HX
Elimination Reaction: Zaitsev’s Rule
Elimination reactions almost always give mixtures of alkene
products
Zaitsev’s rule
• In the elimination of HX from an alkyl halide, the more highly
substituted alkene product predominates
• Used to predict major products
• Formulated in 1875 by the Russian chemist Alexander Zaitsev
Elimination Reaction: Zaitsev’s Rule
Elimination reactions can take place by different
mechanisms
•
E1, E2, and E1cB reactions
•
•
•
Differ in the timing of C-H and C-H bond breaking
All three mechanisms occur in laboratory
E1cB predominates in biological pathways
Elimination Reaction: Zaitsev’s Rule
Elimination Reaction: Zaitsev’s Rule
Worked Example 10.3
Predicting the Product of an Elimination
Reaction
What product would you expect from reaction of
1-chloro-1-methylcyclohexane with KOH in
ethanol?
Worked Example 10.3
Predicting the Product of an Elimination
Reaction
Strategy
• Treatment of an alkyl halide with a strong
base such as KOH yields an alkene
• To find the products in a specific case, locate
the hydrogen atoms on each carbon next to
the leaving group and then generate the
potential alkene products by removing HX in
as many ways as possible
• The major product will be the one that has the
most highly substituted double bond
Worked Example 10.3
Predicting the Product of an Elimination
Reaction
Solution
• The major product is the one that has the most highly
substituted double bond
•
1-methylcyclohexene
10.11 The E2 Reaction
E2 Reaction
•
•
•
Most commonly occurring pathway for
elimination in the laboratory
Occurs when an alkyl halide is treated
with a strong base, such as hydroxide
ion or alkoxide ion (RO-)
Reaction takes place in a single step
through a transition state in which the
double bond begins to form at the same
time the H and X groups are leaving
The E2 Reaction
Evidence to support E2 reaction mechanisms
1. E2 reactions Show second-order kinetics and follow
the rate law:
•
Both base and alkyl halide take part in the ratelimiting step
Rate = k   RX    Base
The E2 Reaction
2.
Deuterium isotope effect
•
A carbon-hydrogen bond is weaker than the
corresponding carbon-deuterium bond
•
•
A C-H bond is more easily broken than an
equivalent C-D bond
The rate of C-H bond cleavage is faster
The E2 Reaction
3.
E2 reactions occur with
periplanar geometry
•
All four reacting atoms
– the hydrogen, the two
carbons, and the
leaving group – lie in
the same plane
•
Anti periplanar
geometry occurs
when the H and the
X are on opposite
sides of the molecule
•
Syn periplanar
geometry occurs
when the H and the
X are on the same
side of the molecule
The E2 Reaction
The sp3 s orbitals in the reactant C-H and C-X bonds
must overlap and become p p orbitals in the alkene
product
• They must overlap in the transition state
•
Occurs most easily if all orbitals are periplanar
The E2 Reaction
Anti periplanar geometry for E2 eliminations has specific
stereochemical consequences
• Meso-1,2-dibromo-1,2-diphenylethane undergoes E2 elimination
on treatment with base to give only the E alkene
•
No Z alkene is formed because the transition state leading to the Z
alkene would have to have syn periplanar geometry and thus be
higher in energy
The E2 Reaction
Anti periplanar geometry is particularly important in
cyclohexane rings where chair geometry forces a
rigid relationship between substituents on adjacent
carbon atoms
•
Only if the hydrogen and the leaving group are trans diaxial can
an E2 reaction occur
Worked Example 10.4
Predicting the Stereochemistry of an E2 Reaction
What stereochemistry do you expect for the
alkene obtained by E2 elimination of (1S,2S)1,2-dibromo-1,2-diphenylethane?
Worked Example 10.4
Predicting the Stereochemistry of an E2 Reaction
Strategy
• Draw (1,2-dibromo-1,2-diphenylethane) so
that you can see its stereochemistry and so
that the –H and –Br groups to be eliminated
are anti periplanar
• Carry out the elimination while keeping all
substituents in approximately their same
positions, and see what alkene results
Worked Example 10.4
Predicting the Stereochemistry of an E2 Reaction
Solution
• Anti periplanar elimination of HBr gives (Z)-1-bromo1,2-diphenylethylene
10.12 The E1 and E1cB Reactions
The E1 Reaction
•
•
•
•
A unimolecular elimination reaction in which
the C-X bond breaks before the C-H bond,
giving a carbocation intermediate
Analogous to
the SN1 reaction
Two steps are
involved in the
reaction, the
first of which is
rate-limiting
Carbocation
intermediate is
present
The E1 and E1cB Reactions
E1 elimination begins with the same unimolecular dissociation as
in the SN1 reaction, but dissociation is followed by loss of H+
from the adjacent carbon rather than by the substitution
E1 and SN1 reactions normally occur together whenever an alkyl
halide is treated in a protic solvent with a nonbasic nucleophile
• The best E1 substrates are also the best SN1 substrates and
mixtures of substitution and elimination products are usually
obtained
• When 2-chloro-2-methylpropane is warmed to 65ºC in 80%
aqueous ethanol, a mixture results
The E1 and E1cB Reactions
E1 mechanisms are supported by evidence
• E1 reactions show first-order kinetics, consistent
with a rate-limiting, unimolecular dissociation
process
• E1 reactions show no deuterium isotope effect
•
Rupture of the C-H (or C-D) bond occurs after the
rate-limiting step rather than during it
• There is no geometric requirement on the E1
reaction
•
The halide and the hydrogen are lost in separate
steps
The E1 and E1cB Reactions
The E1cB Reaction
•
A unimolecular elimination reaction in which the C-H bond
breaks before the C-X bond, giving a carbanion intermediate
• The anion formed expels a leaving group on the adjacent
carbon
• Common in substrates that have a poor leaving group, such
as –OH, two carbons removed from a carbonyl group, HO-CCH-C=O
• Poor leaving group disfavors alternative E1 and E2 reactions
• The carbonyl group makes the adjacent hydrogen unusually
acidic by resonance stabilization of the anion intermediate
10.13 Biological Elimination Reactions
All three elimination reactions – E1, E1cB, and
E2 – occur in various biological pathways
• E1cB mechanism is particularly common
• 3-hydroxy carbonyl compounds are frequently
converted to conjugated unsaturated carbonyl
compounds by elimination reactions
• The substrate is usually an alcohol and the H
atom is usually adjacent to a carbonyl group, just
as in the laboratory
Biological Elimination Reactions
•
Biosynthesis of fats
•
A 3-hydroxybutyryl thioester is dehydrated to the
corresponding unsaturated (crotonyl) thioester
10.14 A Summary of Reactivity:
SN1, SN2, E1, E1cB, and E2
SN1, SN2, E1, E1cB, and E2
• Recognizing trends and making generalizations will
aid in predicting what will happen
Primary alkyl halides
• SN2 substitution occurs if a good nucleophile is used
• E2 elimination occurs if a strong base is used
• E1cB elimination occurs if the leaving group is two
carbons away from a carbonyl group
A Summary of Reactivity:
SN1, SN2, E1, E1cB, and E2
Secondary alkyl halides
•
SN2 substitution occurs if a weakly basic nucleophile is
used in a polar aprotic solvent
• E2 elimination predominates if a strong base used
• E1cB elimination takes place if the leaving group is two
carbons away from a carbonyl group
• SN1 and E1 reactions occur if a weakly basic nucleophile is
used in a protic solvent
Tertiary alkyl halides
•
•
E2 elimination occurs when a base is used
SN1 substitution and E1 elimination occur together under
neutral conditions, such as in pure ethanol or water
• E1cB elimination takes place if the leaving group is two
carbons away from a carbonyl group
Worked Example 10.5
Predicting the Product and Mechanism of a
Reaction
Tell whether each of the following reactions is likely to
be SN1, SN2, E1, E1cB, or E2, and predict the product of
each:
Worked Example 10.5
Predicting the Product and Mechanism of a
Reaction
Strategy
• Look carefully in each reaction at the
substrate, leaving group, nucleophile, and
solvent
• Decide from the summary in Section 10.14
which of reaction is likely to be favored
Worked Example 10.5
Predicting the Product and Mechanism of a
Reaction
Solution
(a) A secondary, nonallylic substrate can undergo an
SN2 reaction with a good nucleophile in a polar
aprotic solvent but will undergo and E2 reaction on
treatment with a strong base
•
In this case E2 reaction is likely to predominate
Worked Example 10.5
Predicting the Product and Mechanism of a
Reaction
(b) A secondary benzylic substrate can undergo an SN2
reaction on treatment with a nonbasic nucleophile in
a polar aprotic solvent and will undergo an E2
reaction on treatment with a base
•
Under protic conditions, such as aqueous formic acid
(HCO2H), an SN1 reaction is likely, along with some
E1 reaction