Organic Chemistry I The Chemistry of Alkyl Halides Unit 10

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Organic Chemistry IThe Chemistry of Alkyl
HalidesUnit 10

• Dr. Ralph C. Gatrone
• Department of Chemistry and Physics
• Virginia State University

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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
  carbon-halogen 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
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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 AlcoholsTertiary 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 AlcoholsPrimary 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 HalidesThe 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
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
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 Waldens 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 kRXNu
• 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
• Ssubstitution
• 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
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

• 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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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 transition-state 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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SubstrateSteric 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 lt Br lt 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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TosylateThe Best Leaving Group

• TsO- supports negative charge
• Resonance stabilized anion

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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 gt 2o gt 1o gtgt 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 kROH
• 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
• 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 kRX

• 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

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Methylations

• S-Adenosylmethionine

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Elimination Reactions

• Elimination is competitive with substitution
• Zaitsevs 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
• ratekR-XB
• Reaction faster with stronger base,
• Reaction faster with better leaving groups

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Transition State
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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)

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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 ReactionsSN1, SN2, E1, E2