Transcript Orbitals - National Taiwan Ocean University

John E. McMurry
http://www.cengage.com/chemistry/mcmurry
Chapter 12
Organohalides: Nucleophilic
Substitutions and Eliminations
Richard Morrison • University of Georgia, Athens
Alkyl Halides
Alkyl halide or haloalkanes
• Compounds with a halogen atom bonded to a saturated sp3hybridized 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
•
Pentahalogenated alkene Halomon, isolated from the red alga
Portieria hornemannii, exhibits anticancer activity against several
human tumor cell lines
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
12.1 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
•
Names shown in parentheses will not be used in this textbook
Naming Alkyl Halides
The carbon-halogen bond of alkyl halides is polarized with the
carbon atom bearing a slight positive charge (d+) and the
halogen a slight negative charge (d-)
• The alkyl halide C-X carbon atom behaves as an
electrophile in polar reactions
Naming Alkyl Halides
Halogens increases in size down the periodic table
• Lengths of corresponding carbon-halogen bonds increase
accordingly
The C-X carbon bond strengths decrease going down the
periodic table
12.2 Preparing Alkyl Halides from Alkenes:
Allylic Bromination
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 from Alkenes:
Allylic Bromination
Alkyl halides can also be prepared from alkenes by reaction with Nbromosuccinimide (NBS) in the presence of light
• Bromine is substituted for hydrogen at the position next to the double
bond – the allylic position
Preparing Alkyl Halides from Alkenes:
Allylic Bromination
Mechanism of allylic bromination
• Br. radical abstracts an allylic hydrogen atom of the alkene
forming an allylic radical plus HBr
• The allylic radical reacts with Br2 to yield the product and a Br.
radical which cycles back to carry on the chain
• Br2 results from reaction of NBS with the HBr formed in the first
step
Preparing Alkyl Halides from Alkenes:
Allylic Bromination
Allylic radicals are more stable than related alkyl radicals by
about 40 kJ/mol (9 kcal/mol) and are more stable than
vinylic radicals by about 85 kJ/mol (19 kcal/mol)
•
According to the Hammond postulate, allylic radicals should form faster
Preparing Alkyl Halides from Alkenes:
Allylic Bromination
•
Allylic radicals are stable due to resonance
Preparing Alkyl Halides from Alkenes:
Allylic Bromination
•
Allylic bromination of an unsymmetrical alkene often leads to a
mixture of products
• Products are not usually formed in equal amounts because the
intermediate allylic radical is not symmetrical and reaction at the
two ends is not equally likely
Preparing Alkyl Halides from Alkenes:
Allylic Bromination
•
Products of allylic bromination reactions are useful for conversion
into conjugated dienes by dehydrohalogenation with base
Worked Example 12.1
Predicting the Product of an Allylic Bromination
Reaction
What products would you expect from the reaction of
4,4-dimethylcyclohexene with NBS?
Worked Example 12.1
Predicting the Product of an Allylic Bromination
Reaction
Strategy
Draw the alkene reactant and identify the allylic positions.
Label the two different allylic positions A and B. Now
abstract an allylic hydrogen from each position to generate
the two corresponding allylic radicals. Each of the two allylic
radicals can add a Br atom at either end (A or a; B or b) to
give a mixture of up to four products. Draw and name the
products
Worked Example 12.1
Predicting the Product of an Allylic Bromination
Reaction
Solution
Reaction at positions B and b are identical so a total of only
three products are formed
12.3 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 from Alcohols
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 from Alcohols
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 acid-catalyzed
rearrangements than the HX method
12.4 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
Alkyl 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
12.5 Discovery of the Nucleophilic
Substitution Reaction
Alkyl halides are electrophiles that react with
nucleophiles/bases in one of two ways
•
Undergo substitution of the X group by the nucleophile
•
Undergo elimination of HX to yield an alkene
12.5 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 (in
Walden’s cycle: 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
• Walden cycle interconverts two
enantiomers of 1-pheylpropan2-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 12.2
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 12.2
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 12.2
Predicting the Stereochemistry of a Nucleophilic
Substitution Reaction
Solution
12.6 The SN2 Reaction
Kinetics
• Study of reaction rates
• In every chemical reaction there is a direct relationship between
the rate at which the reaction occurs and the concentrations of
the reactants
• 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 x [CH3Br] x [-OH]
where
[CH3Br] = CH3Br concentration in molarity
[-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
12.7 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
• The SN2 transition state involves partial bond formation
between the incoming nucleophile and the alkyl halide
carbon atom
•
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) 2-bromopropane
(secondary), and (d) 2-bromo-2-methylpropane (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 HOHalide reactivity order is I-> Br-> ClGoing 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
•
An alcohol can be made more reactive toward nucleophilic
substitution by treating it with p-toluenesulfonyl cholride to
form a tosylate.
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
Example: 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 groundstate energy of the nucleophile, decreasing ∆G‡ and
increasing SN2 reaction rate
12.8 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 2-bromo-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
•
Rate-limiting
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 of inversion
• Reaction of (R)-6-chloro-2,6-dimethyloctane with H2O
• Product is approximately 80% racemized and 20% inverted
(80% R,S + 20% S is equivalent to 40% R and 60% S).
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
12.9 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
Substrate
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 12.3
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 12.3
Predicting the Mechanism of a Nucleophilic
Substitution Reaction
Strategy
•
Look at the substrate, leaving group, nucleophile, and solvent
• Decide from the summaries at the ends of Sections 12.7 and 12.9
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 12.3
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
12.10 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
organodiphosphate 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 Sadenosylhomocysteine
•
S-adenosylmethionine is a biological equivalent of CH3Cl
Biological Substitution Reactions
Biosynthesis of epinephrine from norepinephrin
•
Occurs by an SN2 reaction with S-adenosylmethionine
12.11 Elimination Reactions: 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 Reactions: 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 Reactions: 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 Reactions: Zaitsev’s Rule
Elimination Reactions: Zaitsev’s Rule
Worked Example 12.4
Predicting the Product of an Elimination Reaction
What product would you expect from reaction of 1-chloro1-methylcyclohexane with KOH in ethanol?
Worked Example 12.4
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 12.4
Predicting the Product of an Elimination Reaction
Solution
• The major product is the one that has the most highly
substituted double bond
•
1-methylcyclohexene
12.12 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:
•
Rate = k × RX × Base
Both base and alkyl halide take part in the rate-limiting step
The E2 Reaction
2.
Deuterium isotope effect (supporting evidence for E2
mechanism)
•
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 12.5
Predicting the Stereochemistry of an E2 Reaction
What stereochemistry do you expect for the alkene
obtained by E2 elimination of (1S,2S)-1,2-dibromo1,2-diphenylethane?
Worked Example 12.5
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 12.5
Predicting the Stereochemistry of an E2 Reaction
Solution
• Anti periplanar elimination of HBr gives (Z)-1-bromo-1,2diphenylethylene
12.13 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,
that is two carbons removed from a carbonyl group, HO-C-CH-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
12.14 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
12.15 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 12.6
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 12.6
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 12.15 which of
reaction is likely to be favored
Worked Example 12.6
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 12.6
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