Alkyl Halides

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Lecture 18

• Alkyl Halides
• Chapter 7

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What Is an Alkyl Halide

• An organic compound containing at least one
  carbon-halogen bond (C-X)
• X (F, Cl, Br, I) replaces H
• Can contain many C-X bonds
• Properties and some uses
• Fire-resistant solvents
• Refrigerants
• Pharmaceuticals and precursors

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Naming Alkyl Halides

• 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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Naming with Multiple Halides

• 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 Two Halides or Alkyl Are Equally
Distant from Ends of Chain

• Begin at the end nearer the substituent whose
  name comes first in the alphabet

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Many Alkyl Halides That Are Widely Used Have
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 with slight positive on
  carbon and slight negative on halogen

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Preparing Alkyl Halides

• Alkyl halide is from 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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Reaction of Alkanes with Halogens

• Alkane Cl2 or Br2, heat or light replaces C-H
  with C-X but Gives mixtures
• Hard to control
• Via free radical mechanism
• It is usually not a good idea to plan a synthesis
  that uses this method

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Preparing Alkyl Halides from 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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Preparation of Alkyl Halides from Primary and
Secondary Alcohols

• Specific reagents avoid acid and rearrangements
  of carbon skeleton
• Thionyl chloride converts alcohols into alkyl
  chlorides (SOCl2 ROH ? RCl)
• Phosphorus tribromide converts alcohols into
  alkyl bromides (PBr3 ROH ? RBr)

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Reactions of Alkyl Halides Grignard Reagents

• Reaction of RX with Mg in ether or THF
• Product is RMgX an organometallic compound
  (alkyl-metal bond)
• R is alkyl 1, 2, 3, aryl, alkenyl
• X Cl, Br, I

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Reactions of Grignard Reagents

• Many useful reactions
• RMgX behaves as R- (adds to CO)
• RMgX H3O ? R-H

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Alkyl Halides React with Nucleophiles and Bases

• Alkyl halides are polarized at the carbon-halide
  bond, making the carbon electrophilic
• Nucleophiles will replace the halide in C-X bonds
  of many alkyl halides(reaction as Lewis base)
• Nucleophiles that are Brønsted bases produce
  elimination

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The Nature of Substitution

• Substitution, by definition, requires that a
  "leaving group", which is also a Lewis base,
  departs from the reacting molecule.
• A nucleophile is a reactant that can be expected
  to participate effectively in a substitution
  reaction.

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Substitution Mechanisms

• SN1
• Two steps with carbocation intermediate
• Occurs in 3, allyl, benzyl
• SN2
• Two steps combine - without intermediate
• Occurs in primary, secondary

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Two Stereochemical Modes of Substitution

• Substitution with inversion

• Substitution with retention

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The SN2 Reaction

• Reaction is with inversion at reacting center
• Follows second order reaction kinetics
• Nomenclature to describe characteristic step
• Ssubstitution
• N (subscript) nucleophilic
• 2 both nucleophile and substrate in
  characteristic step (bimolecular)

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SN2 Process

• The reaction involves a transition state in which
  both reactants are together

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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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Characteristics of the SN2 Reaction

• 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 CC (vinyl halides)

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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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Order of Reactivity in SN2

• The more alkyl groups connected to the reacting
  carbon, the slower the reaction
• Difficult for nucleophile to approach, steric
  strain in T.S.

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The Nucleophile

• Neutral or negatively charged Lewis base
• Reaction increases coordination at nucleophile
• Neutral nucleophile acquires positive charge
• Anionic nucleophile becomes neutral
• See Table 7-1 for an illustrative list

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Relative Reactivity of Nucleophiles

• Depends on reaction and conditions
• More basic nucleophiles react faster
• 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

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Poor Leaving Groups

• If a group is very basic or very small, it is
  prevents reaction

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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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SN1 Energy Diagram
Step through highest energy point is
rate-limiting (k1 in forward direction)
k1
k-1
k2
V kRX

• Rate-determining step is formation of carbocation

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Rate-Limiting Step

• The overall rate of a reaction is controlled by
  the rate of the slowest step
• The rate depends on the concentration of the
  species and the rate constant of the step
• The highest energy transition state point on the
  diagram is that for the rate determining step
  (which is not always the highest barrier)
• This is the not the greatest difference but the
  absolute highest point

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Stereochemistry of SN1 Reaction

• The planar intermediate leads to loss of
  chirality
• A free carbocation is achiral
• Product is racemic or has some inversion

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Delocalized Carbocations

• Delocalization of cationic charge enhances
  stability
• Primary allyl is more stable than primary alkyl
• Primary benzyl is more stable than allyl

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Characteristics of the SN1 Reaction

• Tertiary alkyl halide is most reactive by this
  mechanism
• Controlled by stability of carbocation

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Allylic and Benzylic Halides

• Allylic and benzylic intermediates stabilized by
  delocalization of charge
• Primary allylic and benzylic are also more
  reactive in the SN2 mechanism

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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

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Nucleophiles in SN1

• Since nucleophilic addition occurs after
  formation of carbocation, reaction rate is not
  affected normally affected by nature or
  concentration of nucleophile

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Alkyl Halides Elimination

• Elimination is an alternative pathway to
  substitution
• Opposite of addition
• Generates an alkene
• Can compete with substitution and decrease yield,
  especially for SN1 processes

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Zaitsevs Rule for Elimination Reactions (1875)

• In the elimination of HX from an alkyl halide,
  the more highly substituted alkene product
  predominates

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Mechanisms of Elimination Reactions

• Ingold nomenclature E elimination
• E1 X- leaves first to generate a carbocation
• a base abstracts a proton from the carbocation
• E2 Concerted transfer of a proton to a base and
  departure of leaving group

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The E2 Reaction Mechanism

• A proton is transferred to base as leaving group
  begins to depart
• Transition state combines leaving of X and
  transfer of H
• Product alkene forms stereospecifically

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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
• VkR-XB
• Reaction goes faster with stronger base, better
  leaving group

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Geometry of Elimination E2

• Antiperiplanar allows orbital overlap and
  minimizes steric interactions

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E2 Stereochemistry

• Overlap of the developing ? orbital in the
  transition state requires periplanar geometry,
  anti arrangement

Allows orbital overlap
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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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The E1 Reaction

• Competes with SN1 and E2 at 3 centers
• V 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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For Next Class

• Read Chapter 8
• Alcohols, phenols and ethers