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Organic Chemistry I
The Chemistry of Alkyl Halides
Unit 10
Dr. Ralph C. Gatrone
Department of Chemistry and Physics
Virginia State University
Fall, 2009
1
Objectives
• Nomenclature
• Preparation
• Reactions
– Organometallic Reagents
– Nucleophilic Substitution Reactions
– Elimination Reactions
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What Is an Alkyl Halide?
• An organic compound containing at least one carbonhalogen bond (C-X)
– X = F, Cl, Br, I
• Can contain many C-X bonds
– Entirely halogenated = perhalo
• Wide-spread in nature
• Common industrial chemicals
• Properties and some uses
–
–
–
–
Fire-resistant solvents
Refrigerants
Pesticides
Pharmaceuticals and precursors
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Nomenclature
• Name is based on longest carbon chain
– (Contains double or triple bond if present)
– Number from end nearest any substituent (alkyl
or halogen)
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Nomenclature with Multiple Halogen
• If more than one of
the same kind of
halogen is present,
use prefix di, tri,
tetra
• If there are several
different halogens,
number them and
list them in
alphabetical order
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Naming if Halides Are Equidistant
• Begin at the end nearer the substituent
whose name comes first in the alphabet
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Common Names
•
•
•
•
•
Chloroform
Carbon tetrachloride
Methylene chloride
Methyl iodide
Trichloroethylene
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Structure of Alkyl Halides
• C-X bond is longer as you go down periodic table
• C-X bond is weaker as you go down periodic table
• C-X bond is polarized
– some positive charge on carbon
– some negative charge on halogen
• The carbon is an electrophilic center
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Electrophilic Carbon
C
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X
9
Preparation
• Alkyl halide - addition of HCl, HBr, HI to alkenes to give
Markovnikov product (see Alkenes chapter)
• Alkyl dihalide from anti addition of bromine or chlorine
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Allylic Bromination of Alkenes
• N-bromosuccinimide (NBS) selectively
•
•
brominates allylic positions
Requires light for activation
A source of dilute bromine atoms
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Use of Allylic Bromination
• Bromination with NBS creates an allylic bromide
• Reaction of an allylic bromide with base
produces a conjugated diene, useful in synthesis
of complex molecules
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Alkyl Halides from Alcohols
Tertiary Alcohols
• Reaction of tertiary C-OH with HX is fast and effective
– Add HCl or HBr gas into ether solution of tertiary alcohol
• Primary and secondary alcohols react very slowly and
often rearrange, so alternative methods are used
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Alkyl Halides from Alcohols
Primary and Secondary Alcohols
• Specific reagents avoid acid and rearrangements of
carbon skeleton
• Thionyl chloride converts alcohols into alkyl chlorides
– SOCl2 : ROH to RCl
• Phosphorus tribromide converts alcohols into alkyl
bromides
– PBr3: ROH to RBr
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Reactions of Alkyl Halides
The Grignard Reagent
• RX reacts with Mg in ether or THF
• Product is RMgX
–
–
–
–
an organometallic compound
alkyl-metal bond
R : alkyl (1°, 2°, 3°), aryl, alkenyl
X = Cl, Br, I
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The Grigard Reagent
C
X
C
MgX
Polarity is reversed
Electrophilic Carbon becomes Nucleophilic Carbon
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Organo-Metallic Compounds
• RX + Zn gives R2Zn
• RX + Li gives RLi
• RX + Al gives R3Al
• Behave similar to Grignard
• Others use RLi
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Organo-Metallics
• RLi + CuI gives R2CuLi
– Organocuprate
– Useful coupling reaction
• R2CuLi + RX gives R-R
• RLi + CdCl2 gives R2Cd
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Observations
CO2H
HO2C
PCl5
CO2H
HO2C
Cl
OH
(+)-chlorosuccinic acid
(-)-malic acid
(-2.3)
Ag2O
Ag2O
PCl5
CO2H
HO2C
Cl
(-)-chlorosuccinic acid
CO2H
HO2C
OH
(+)-malic acid
(+2.3)
Optical rotation is related to chirality
Optical rotation and chirality are changing
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Significance of the Walden
Inversion
• Stereochemistry at the chiral C is inverted
• The reactions involve substitution at that center
•
•
by a nucleophile
Therefore, nucleophilic substitution appears to
invert the configuration at a chiral center
The presence of carboxyl groups in malic acid
led to some dispute as to the nature of the
reactions in Walden’s cycle
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Stereochemistry of Nucleophilic Substitution
• Isolate step so we know
•
•
what occurred (Kenyon
and Phillips, 1929) using
1-phenyl-2-propanol
Only the second and fifth
steps are reactions at
carbon
Inversion occurs during
the substitution step
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Kinetics
• Review Chapter 5
• Reactions are considered fast or slow
• How fast is given by reaction rate
• Reaction rates are measurable
• Relationship between rate and
concentration
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CH3Br + HO-
CH3OH + Br-
• Rate determined at given temp and [conc]
• Double [HO-] – rate doubles
• Double [CH3Br] – rate doubles
• Double both – rate increases by 4X
• Rate is dependent upon both [reactants]
– Second order kinetics
– Rate = k[RX][Nu]
• k is the rate constant
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What We Know
• Substitution reaction
• Inversion of stereochemistry
• Second-order kinetics
• Proposed mechanism SN2
• Substitution, nucleophilic, bimolecular
• Single step from SM to Product
• Primary and secondary alkyl halides
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The SN2 Reaction
• Reaction - inversion at reacting center
• Follows second order reaction kinetics
• Ingold nomenclature to describe characteristic
step:
– S=substitution
– N (subscript) = nucleophilic
– 2 = both nucleophile and substrate in
characteristic step (bimolecular)
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SN2 Process
• The reaction must involve a transition state in
which both reactants are together
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Mechanism
CH3OH + Br-
[TS]
CH3Br + HO-
[TS]
=
[ Nu
C
LG
]
Nu attacks from opposite face as
leaving group departs leading to
inversion of stereochemistry
Substrate and nucleophile appear
in rate determining step
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SN2 Transition State
• The transition state of an SN2 reaction has a
planar arrangement of the carbon atom and the
remaining three groups
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Additional Observations:
SN2 Reaction
•
•
•
•
•
•
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Sensitive to steric effects
Methyl halides are most reactive
Primary are next most reactive
Secondary might react
Tertiary are unreactive by this path
No reaction at C=C (vinyl halides)
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Influencing a Reaction
• To increase the rate of a reaction
– raise the energy of the reactants
– lower the energy of the transition state
• To slow a reaction,
– Lower the energy of the reactants
– Raise the energy of the transition state
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Reactant and Transition-state Energy
Levels Affect Rate
Higher reactant
energy level (red
curve) = faster
reaction (smaller
G‡).
Higher transitionstate energy level
(red curve) =
slower reaction
(larger G‡).
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Variables that Influence the Reaction
• Substrate
• Nucleophile
• Leaving Group
• Solvent
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Substrate
Steric Effects on SN2 Reactions
The carbon atom in (a) bromomethane 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.
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Substrate: Transition State
• In the Transition State
– Bonds between C and Nu are forming
– Bonds between C and LG are breaking
– Approach to hindered C raises TS energy
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Substrate: Transition State Energy
Very hindered
• Steric effects destabilize transition states
• Severe steric effects can also destabilize
ground state
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Substrate: Order of Reactivity in SN2
• The more alkyl groups connected to the reacting
carbon, the slower the reaction
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Substrate
• Aryl – do not react
• Vinyl – do not react
• Recall: acetylide anion reacts with methyl
or primary alkyl halides
– Better bases lead to elimination reactions
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Nucleophile
• Neutral or negatively charged Lewis bases
• Reaction increases coordination at nucleophile
– Neutral nucleophile acquires positive charge
– Anionic nucleophile becomes neutral
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Nucleophiles
• Depends on reaction and conditions
• Nucleophilicity parallels basicity
• Nucleophilicity increases down a group in the
•
periodic table (Cl < Br < I)
Anions are usually more reactive than neutrals
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The Leaving Group
• A good leaving group reduces the barrier to a reaction
• Stable anions that are weak bases are usually excellent
•
leaving groups and can delocalize charge
Negative charge builds in LG
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Tosylate
The Best Leaving Group
• TsO- supports negative charge
• Resonance stabilized anion
O
S
O
S
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O
S
O
O
H3C
O
O
H3C
O
O
H3C
41
Poor Leaving Groups
• If a group is very basic or very small, it prevents
the reaction from occurring
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The Solvent
• Solvents that can donate hydrogen bonds (-OH or –NH)
slow SN2 reactions by associating with reactants
• Energy is required to break interactions between
reactant and solvent
• Polar aprotic solvents (no NH, OH, SH) form weaker
interactions with substrate and permit faster reaction
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Protic Polar Solvents
• Protic polar solvents bind to X• Hydrogen Bonding
• Solvent cage around nucleophile
• Stabilizes negative charge
• Lowering ground state energy
• Increases rate of reaction
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Aprotic Polar Solvents
• Bind to M+
• X- is unsolvated
– More reactive
– At a higher energy
– Decreases rate of reaction
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SN2 Review
• Favored
– Basic Nu:
– By aprotic polar solvents
– Stable anions as leaving groups
• Disfavored
– In protic solvents (water, alcohol)
• Sensitive to steric factors
• Second Order Kinetics
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ROH + HX RX + H2O
• Observations
– 3o > 2o > 1o >> CH3
– Protic solvent used
– Acidic to neutral conditions utilized
– Non-basic nucleophiles
• Substitution by nucleophile
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ROH + HX RX + H2O
• Rate is affected by changes in [ROH]
• Rate is unaffected by changes in [H2O]
• Rate expression
– Rate = k[ROH]
– First Order Kinetics
– Rate Determining Step involves ROH not Nu
– Rate Determining Step is slowest step of
reaction and nothing occurs slower
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Mechanism
• Data suggests:
slow
RX
nucleophile
intermediate
fast
R-Nu
• Intermediate = R+
•
•
(carbocation)
SN1 mechanism
R+ reacts fast with Nu
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SN1 Energy Diagram
Step through highest energy
point is rate-limiting (k1 in
forward direction)
Rate = k[RX]
• Rate-determining step is
formation of carbocation
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The SN1 Reaction
• Tertiary alkyl halides react rapidly in protic
•
•
solvents by a mechanism that involves departure
of the leaving group prior to addition of the
nucleophile
Called an SN1 reaction – occurs in two distinct
steps while SN2 occurs with both events in same
step
If nucleophile is present in reasonable
concentration (or it is the solvent), then
ionization is the slowest step
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Stereochemistry
• Reaction involves carbocation
• Carbocation is sp2 hybridized
• Carbocation is planar
• Expect to see racemization of any chiral C
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Stereochemistry of SN1 Reaction
• The planar
intermediate
leads to loss of
chirality
– A free
carbocation is
achiral
• Product should
be racemic
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SN1 in Reality
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SN1 in Reality
• Carbocation is biased to react on side opposite
leaving group
• Suggests reaction occurs with carbocation
loosely associated with leaving group during
nucleophilic addition
• Alternative that SN2 is also occurring is unlikely
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Proposed Mechanism
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Effect of Ion Pair Formation
• If leaving group remains associated, then
product has more inversion than retention
• Product is only partially racemic with more
inversion than retention
• Associated carbocation and leaving group is
an ion pair
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Variables that Influence the
Reaction
• Substrate
• Nucleophile
• Leaving Group
• Solvent
We will examine each one separately.
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Substrate
• Hammond Postulate
• Stabilize a high energy intermediate you
stabilize the transition state leading to it
• More stable R+ favors SN1 Reaction
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Substrate
• Tertiary alkyl halide is most reactive
by this mechanism
• Controlled by stability of carbocation
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Effect of Leaving Group on SN1
• Critically dependent on leaving group
– Reactivity: the larger halides ions are better leaving groups
• In acid, OH of an alcohol is protonated and leaving
•
•
group is H2O, which is still less reactive than halide
p-Toluensulfonate (TosO-) is excellent leaving group
Stable negative charge better LG
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Nucleophiles in SN1
• Since nucleophilic addition occurs after
formation of carbocation, reaction rate is
not affected by nature or concentration of
nucleophile
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Solvent
• Is Critical in SN1
• Stabilizing carbocation also stabilizes
associated transition state and controls
rate
Solvation of a carbocation by
water
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Polar Solvents Promote Ionization
• Polar, protic and unreactive Lewis base solvents
facilitate formation of R+
• Reaction is faster in polar solvents
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Effects of Solvent on Energies
• Polar solvent stabilizes transition state and
intermediate more than reactant and product
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Substitution in Biological Systems
• SN2 and SN1 observed
• Substrate is generally an organo diphosphate
O
C
O
P
O
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O
O
P
O
O
Mg++
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Methylations
• S-Adenosylmethionine
NH2
-O
2C
H
NH3+
CH3
N
S
+
N
N
N
OH OH
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Elimination Reactions
substitution
Nu
X
nucleophile/base
H
H
alkyl halide
elimination
• Elimination is competitive with substitution
• Zaitsev’s rule dominates – the most substituted
•
alkene generally forms
Three mechanisms for elimination will be
considered (E1, E2, and E1cB)
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E2 Reaction Kinetics
• One step – rate law has base and alkyl halide
• Transition state bears no resemblance to
•
•
•
reactant or product
rate=k[R-X][B]
Reaction faster with stronger base,
Reaction faster with better leaving groups
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Transition State
base-H bond forming
base
C-C pi bond forming
H
X
C-X bond breaking
H-C bond breaking
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Geometry of Elimination – E2
• Antiperiplanar (proton and LG) allows maximum
orbital overlap and minimizes steric interactions
• Allows us to predict product formed.
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E2 Stereochemistry
• Overlap of the developing  orbital in the
•
•
transition state requires periplanar geometry,
anti arrangement
Allows maximum orbital overlap
Stereospecific reaction
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Predicting Product
• E2 is stereospecific
• Meso-1,2-dibromo-1,2-diphenylethane with base gives
•
cis 1,2-diphenyl
RR or SS 1,2-dibromo-1,2-diphenylethane gives trans
1,2-diphenyl
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Elimination From Cyclohexanes
• Abstracted proton and leaving group should
•
align trans-diaxial to be anti periplanar in
approaching transition state
Equatorial groups are not in proper alignment
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The E1 Reaction Mechanism
• Competes with SN1 and E2 at 3° centers
• Rate = k [RX]
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Stereochemistry of E1 Reactions
• E1 is not stereospecific and there is no
•
requirement for alignment
Product has Zaitsev orientation because step
that controls product is loss of proton after
formation of carbocation
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Comparing E1 and E2
• Strong base is needed for E2 but not for E1
• E2 is stereospecifc, E1 is not
• E1 gives Zaitsev orientation
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EcB1 Mechanism
•
•
•
•
Intermediate is a carbanion
Base removal of H+ is rate determining
Anion is formed
Common with poor leaving groups (OH)
OH
O
OH
_
O
O
base
H
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Elimination in Biological Systems
• EcB1 mechanism is most common
• E1 and E2 occur less often
• 3-hydroxy carbonyls convert into
unsaturated carbonyl compounds
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Summary of Reactions
SN1, SN2, E1, E2
1o RX
SN2
E2
SN1
E1
favored with good nucleophiles
favored with strong (hindered) bases
never observed
never observed
2o RX
SN2
E2
mixtures from both mechanisms
are often observed
SN2
predominates in aprotic polar solvents
and with good Nu and weak bases
E2
predominates with strong bases
3o RX
SN2
E2
SN1
never observed
favored with strong bases
mixtures due to E1 observed
under non-basic conditions
mixtures due to SN1 observed
under non-basic conditions
E1
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