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04/12/2014
1
Alkyl Halides: Nucleophilic
Organic Chemistry
y pSubstitution and Elimination
Lecture November 13, 2014
Dr. Edi Munawar
Edi Munawar
Jurusan Teknik Kimia - Fakultas TeknikUniversitas Syiah Kuala
contact: [email protected]
Classes of Halides
• Alkyl halides: Halogen, C
H
H C
H
Bry gX, is directly bonded to sp3 carbon.
• Vinyl halides: X is bonded to sp2 carbon of alkene.
C CH
H
H
Cl
vinyl halide
CH
H
C
H
Br
alkyl halide
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• Aryl halides: X is bonded to sp2 carbon on benzene ring.
vinyl halideI
aryl halide
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Polarity and Reactivity
• Halogens are more electronegative than C.
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• Carbon—halogen bond is polar, so carbon has partial positive charge.
• Carbon can be attacked by a nucleophile.
• Halogen can leave with the electron pair. 3
IUPAC Nomenclature
• Name as haloalkaneName as haloalkane.
• Choose the longest carbon chain, even if the halogen is not bonded to any of those C’s.
• Use lowest possible numbers for position.
CH CH CH CHCH CH CH
CH2CH2F1 2
CH CHCH CH
Cl
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CH3CH2CH2CHCH2CH2CH331 2 4
2-chlorobutane 4-(2-fluoroethyl)heptane
1CH3CHCH2CH3
2 3 4 5 6 7
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Examples
BrCH3
CH3CHCH2CH2CH2CHCH2CH2CH3
Br
H
1
6-bromo-2-methylnonane 1
3
2 3 4 5 6 7 8 9
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F H3
cis-1-bromo-3-fluorocyclohexane
Systematic Common Names
• The alkyl groups is a substituent on halide.
• Useful only for small alkyl groups.
CH3CHCH2
CH3
Br CH3CH2CH
CH3
Br CH3C
CH3
Br
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CH3
iso-butyl bromide sec-butyl bromide tert-butyl bromide
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Common Names of Halides
• CH2X2 called methylene halideCH2X2 called methylene halide.• CHX3 is a haloform.• CX4 is carbon tetrahalide.• Common halogenated solvents:
CH2Cl2 is methylene chlorideCHCl is chloroform
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CHCl3 is chloroform CCl4 is carbon tetrachloride.
Alkyl Halides Classification
• Methyl halides: halide is attached to a methyl groupgroup.
• Primary alkyl halide: carbon to which halogen is bonded is attached to only one other carbon.
• Secondary alkyl halide : carbon to which halogen is bonded is attached to two other carbons.
• Tertiary alkyl halide : carbon to which
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Tertiary alkyl halide : carbon to which halogen is bonded is attached to three other carbon.
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Primary, Secondary, Tertiary Alkyl Halides
CH3 CH3
primary alkyl halide secondary alkyl halide
CH3CHCH2
CH3
Br CH3CH2CH
CH3
Br
CH3C
CH3
Br*
**
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tertiary alkyl halide
CH3C Br
CH3
Types of Dihalides
• Geminal dihalide: Brtwo halogen atoms are bonded to the same carbon.
• Vicinal dihalide: two halogen atoms
b d d t
CH3 CH Br
CH2CH2Br Br
geminal dihalide
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are bonded to adjacent carbons.
2 2
vicinal dihalide
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Uses of Alkyl Halides
• Industrial and household cleaners.• Anesthetics:
CHCl d i i ll l th ti b t it• CHCl3 used originally as general anesthetic but it is toxic and carcinogenic.
• CF3CHClBr is a mixed halide sold as Halothane® • Freons are used as refrigerants and foaming agents.
• Freons can harm the ozone layer so they have been replaced by low-boiling hydrocarbons or carbon dioxide.
P i id h DDT l i
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• Pesticides such as DDT are extremely toxic to insects but not as toxic to mammals. • Haloalkanes can not be destroyed by bacteria so
they accumulate in the soil to a level which can be toxic to mammals, especially, humans.
Dipole Moments
• Electronegativities of the halides:F > Cl > B > IF > Cl > Br > I
• Bond lengths increase as the size of the halogen increases:
C—F < C—Cl < C—Br < C—I• Bond dipoles:
C—Cl > C—F > C—Br > C—I1.56 D 1.51 D 1.48 D 1.29 D
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1.56 D 1.51 D 1.48 D 1.29 D
• Molecular dipoles depend on the geometry of the molecule.
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Boiling Points
• Greater intermolecular forces, higher b.p.• dipole-dipole attractions not significantly different
for different halides
• London forces greater for larger atoms
• Greater mass, higher b.p.
• Spherical shape decreases b.p.
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(CH3)3CBr CH3(CH2)3Br
73C 102C
Densities
• Alkyl fluorides and chlorides less dense• Alkyl fluorides and chlorides less dense than water.
• Alkyl dichlorides, bromides, and iodides more dense than water.
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Preparation of Alkyl Halides
• Free radical halogenation (Chapter 4)• Chlorination produces a mixtures of
products. This reaction is not a good lab synthesis, except in alkanes where all hydrogens are equivalent.
• Bromination is highly selective.
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• Free radical allylic halogenation• Halogen is placed on a carbon directly
attached to the double bond (allylic).
Halogenation of Alkanes
• Bromination is highly selective:
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3º carbons > 2º carbons > 1º carbons
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Allylic Halogenation
• Allylic radical is resonance stabilized.
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Allylic radical is resonance stabilized.
• Bromination occurs with good yield at the allylic position (sp3 C next to C C).
N-bromosuccinimide
• N-bromosuccinimide (NBS) is an allylic
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brominating agent.
• Keeps the concentration of Br2 low.
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Reaction Mechanism
• The mechanism involves an allylic radical stabilized by resonance
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stabilized by resonance.
• Both allylic radicals can react with bromine.
Substitution Reactions
• The halogen atom on the alkyl halide is replaced with a nucleophile (Nuc-)
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a nucleophile (Nuc ).• Since the halogen is more electronegative than
carbon, the C—X bond breaks heterolytically and X-
leaves.
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Elimination Reactions
• Elimination reactions produce double bonds.
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• The alkyl halides loses a hydrogen and the halide.
• Also called dehydrohalogenation (-HX).
SN2 Mechanism
• Bimolecular nucleophilic substitution.
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• Concerted reaction: new bond forming and old bond breaking at same time.• Rate is first order in each reactant.• Walden inversion.
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SN2 Energy Diagram
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• The SN2 reaction is a one-step reaction.
• Transition state is highest in energy. 23
Uses for SN2 Reactions
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SN2: Nucleophilic Strength
• Stronger nucleophiles react faster.• Strong bases are strong nucleophiles, but not
all strong nucleophiles are basic.
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Basicity versus Nucleophilicity
B i it i d fi d b th ilib i t t
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• Basicity is defined by the equilibrium constant for abstracting a proton.
• Nucleophilicity is defined by the rate of attack on the electrophilic carbon atom
26
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Trends in Nucleophilicity
• A negatively charged nucleophile is stronger th it t l t tthan its neutral counterpart:
OH- > H2O HS-> H2S NH2- > NH3
• Nucleophilicity decreases from left to right : OH- > F- NH3 > H2O
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• Increases down Periodic Table, as size and polarizability increase:
I- > Br- > Cl-
Polarizability Effect
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Bigger atoms have a soft shell which can start to overlap the carbon atom from a farther distance.
28
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Solvent Effects: ProticSolvents
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• Polar protic solvents have acidic hydrogens (O—H or N—H) which can solvate the nucleophile reducing their nucleophilicity.
• Nucleophilicity in protic solvents increases as the size of the atom increases.
29
Solvent Effects: AproticSolvents
• Polar aprotic solvents do not have acidic protons and
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• Polar aprotic solvents do not have acidic protons and therefore cannot hydrogen bond.
• Some aprotic solvents are acetonitrile, DMF, acetone, and DMSO.
30
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Crown Ethers
• Crown ethers solvate the cation, so the nucleophilicstrength of the anion increases.
• Fluoride becomes a d l hil
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good nucleophile.
Leaving Group AbilityThe best leaving groups are:• Electron-withdrawing, to polarize the carbon atom.• Stable (not a strong base) once it has left.• Polarizable, to stabilize the transition state.
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Structure of Substrate on SN2 Reactions
• Relative rates for SN2: N
CH3X > 1° > 2° >> 3°
• Tertiary halides do not react via the SN2 mechanism, due to steric hindrance.
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Steric Effects of the Substrate on SN2 Reactions
• Nucleophile approaches from the back side.
• It must overlap the back lobe of the C—X sp3
orbital.
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Stereochemistry of SN2
SN2 reactions will result in an inversion of configuration also called a Walden inversion.
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The SN1 Reaction
• The SN1 reaction is a unimolecular N
nucleophilic substitution.
• It is a two step reaction with a carbocation intermediate.
• Rate is first order in the alkyl halide, d i th l hil
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zero order in the nucleophile.
• Racemization occurs.
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SN1 Mechanism: Step 1
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Formation of carbocation (rate determining step)
37
SN1 Mechanism: Step 2
• The nucleophile attacks the carbocation, f i th d t
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forming the product.• If the nucleophile was neutral, a third step
(deprotonation) will be needed.
38
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SN1 Energy Diagram
• Forming the carbocation is an endothermic step.
• Step 2 is fast with a low activation energy
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energy.
39
Rates of SN1 Reactions
• Order of reactivity follows stability of carbocations (opposite to SN2)• 3° > 2° > 1° >> CH3X
• More stable carbocation requires less energy to form.
• A better leaving group will increase the
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• A better leaving group will increase the rate of the reaction.
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Solvation Effect
• Polar protic solvent best because it can solvate both ions strongly through hydrogen bonding.
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Structure of the Carbocation
• Carbocations are sp2 hybridized and trigonal planar.
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p y g pThe lobes of the empty p orbital are on both sides of the trigonal plane.
• Nucleophilic attack can occur from either side producing mixtures of retention and inversion of configuration if the carbon is chiral.
42
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Stereochemistry of SN1
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The SN1 reaction produces mixtures of enantiomers.There is usually more inversion than retention ofconfiguration
43
Rearrangements
• Carbocations can rearrange to form a more stable carbocation.
• Hydride shift: H- on adjacent carbon bonds with C+.
• Methyl shift: CH3- moves from adjacent
b if h d il bl
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carbon if no hydrogens are available.
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Hydride and Methyl Shifts
• Since a primary carbocation cannot form, the methyl
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group on the adjacent carbon will move (along with both bonding electrons) to the primary carbon displacing the bromide and forming a tertiary carbocation.
• The smallest groups on the adjacent carbon will move: if there is a hydrogen it will give a hydride shift.45
SN1 or SN2 Mechanism?
SN2 SN1
CH3X > 1º > 2º 3º > 2º
Strong nucleophile Weak nucleophile (may also be solvent)
Polar aprotic solvent Polar protic solvent.
Rate = k[alkyl halide][Nuc] Rate = k[alkyl halide]
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Rate k[alkyl halide][Nuc] Rate k[alkyl halide]
Inversion at chiral carbon Racemization
No rearrangements Rearranged products
46
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The E1 Reaction
• Unimolecular elimination.• Two groups lost: a hydrogen and the
halide.• Nucleophile acts as base.• The E1 and SN1 reactions have the
same conditions so a mixture of
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same conditions so a mixture of products will be obtained.
E1 Mechanism
Step 1: halide ion leaves forming a carbocation
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• Step 1: halide ion leaves, forming a carbocation.• Step 2: Base abstracts H+ from adjacent carbon
forming the double bond.
48
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A Closer Look
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E1 Energy Diagram
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• The E1 and the SN1 reactions have the same first step: carbocation formation is the rate determining step for both mechanisms.
50
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Double Bond Substitution Patterns
• The more substituted double bond is more stable.
tetrasubstituted trisubstituted disubstituted monosubstituted
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• In elimination reactions, the major product of the reaction is the more substituted double bond: Zaitsev’s Rule.
Zaitsev’s Rule
• If more than one elimination product is possible, the most-substituted alkene is the major product (most stable).
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major product(trisubstituted)
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The E2 Reaction
• Elimination, bimolecular
• Requires a strong base
• This is a concerted reaction: the proton is abstracted, the double bond forms and the leaving group leaves, all in one t
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step.
The E2 Mechanism
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• Order of reactivity for alkyl halides: 3° > 2 ° > 1°
• Mixture may form, but Zaitsev productpredominates.
54
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E2 Stereochemistry
• The halide and the proton to be abstracted must be anti-coplanar (=180º) to each other for the elimination to occur.
• The orbitals of the hydrogen atom and the halide must be aligned so they can begin to form a pi bond in the transition state.
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• The anti-coplanar arrangement minimizes any steric hindrance between the base and the leaving group.
E2 Stereochemistry
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E1 or E2 Mechanism?
• Tertiary > Secondary • Tertiary > Secondary
• Base strength unimportant (usually weak)
• Good ionizing solvent
• Rate = k[alkyl halide]
• Zaitsev product
• Strong base required
• Solvent polarity not important.
• Rate =k[alkylhalide][base]
• Zaitsev product
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Zaitsev product
• No required geometry
• Rearranged products
p
• Coplanar leaving groups (usually anti)
• No rearrangements
57
Substitution or Elimination?
• Strength of the nucleophile determines order: Strong nucleophiles or bases promote bimolecular reactions.
• Primary halide usually undergo SN2.
• Tertiary halide mixture of SN1, E1 or E2. Th t d S 2
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They cannot undergo SN2.
• High temperature favors elimination.
• Bulky bases favor elimination.
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Secondary Alkyl Halides
• Secondary alkyl halides are more challenging:• Strong nucleophiles will promote S 2/E2• Strong nucleophiles will promote SN2/E2• Weak nucleophiles promote SN1/E1
• Strong nucleophiles with limited basicity favor SN2. Bromide and iodide are good examples of these.
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Problem 1
Predict the mechanisms and products of the following reaction:
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Solution Problem 1
There is no strong base or nucleophile present, so thisti t b fi t d ith i i ti f threaction must be first order, with an ionization of the
alkyl halide as the slow step. Deprotonation of thecarbocation gives either of two elimination products,and nucleophilic attack gives a substitution product.
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Problem 2
Predict the mechanisms and products of the following reaction:
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Solution Problem 2
This reaction takes place with a strong base, so it isd d Thi d h lid d b thsecond order. This secondary halide can undergo both
SN2 substitution and E2 elimination. Both products willbe formed, with the relative proportions of substitutionand elimination depending on the reaction conditions.
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