Chemistry 331 - Fall 1996
Elements of Organic Chemistry I

Professor Carl C. Wamser

Chapter 7 - Alkyl Halides

Alkyl Halides

• Functional group: C-X bond
• X = halogen
  F (fluoro)
  Cl (chloro)
  Br (bromo)
  I (iodo)

Nomenclature

• same IUPAC rules as for other substituents (like alkyls)
• common names: alkyl halide
  ethyl chloride
  isopropyl iodide
  benzyl bromide
  

Chlorination of Alkanes

• CH4 + Cl2 --(hv)--> CH3Cl + HCl
• R-H + X2 --(hv)--> R-X + HX
• replacement of H by halogen
• initiated by light (or heat)
• works best for Cl2
• slow for Br2
• unreactive with I2
• explosive with F2

Chlorination Products

• not very useful synthetically
• usually multiple products
  e.g., CH4 --> CH3Cl --> CH2Cl2 --> CHCl3 --> CCl4

Chlorination Mechanism

• radical chain mechanism
  (like polymerization)
• initiation (generation of radicals)
• propagation (reaction of radicals)
  products are generated in these steps
  net reaction is the sum of these steps
• termination (loss of radicals)

Chlorination Mechanism

• Initiation:
  Cl-Cl + hv ----> 2 Cl·
• Propagation:
  Cl· + CH4 ----> CH3· + H-Cl
  CH3· + Cl-Cl ----> CH3-Cl + Cl·
  (repeat the propagation steps)
• Termination:
  e.g., 2 CH3· ---> CH3CH3 (minor product)

Alcohols to Alkyl Halides

• R-OH + HX ----> R-X + H2O
  works best for 3° alcohols
• 1° and 2° alcohols converted by:
  R-OH --(SOCl2)--> R-Cl
  R-OH --(PBr3)--> R-Br

Grignard Reagents

• R-X + Mg ----> R-Mg-X
• works for almost all R groups
• works for X = Cl, Br, I
• makes a nucleophilic C
• reacts with electrophiles
• RMgX + H2O ----> RH
  (many more reactions later)
  

Nucleophilic Substitution

• R-X + Nu:- ----> R-Nu + X:-
• replacement of X- (a leaving group)
• X- often halide
• wide variety of nucleophiles
• very versatile synthetic reaction

Recognizing Nucleophiles

• must have a pair of electrons
• often have a negative charge
• often are basic
• larger halides are better nucleophiles
• I- > Br- > Cl- > F-

The SN2 Mechanism

• concerted (single step)
• involves backside attack
  (simultaneous bond-making and bond-breaking)

SN2 Mechanism - Evidence

• reaction rate proportional to concentration of both reactants
  Rate = k [RX] [Nu]
• kinetics are second-order
• mechanism is bimolecular

SN2 Mechanism - Evidence

• stereochemistry is inverted
• indicates backside attack

SN2 Mechanism - R Groups

• bulky R groups react much slower
• reactivity order in SN2:
  CH3 > 1° > 2° > 3°
• steric hindrance to attack by the nucleophile slows the rate
  n-Bu > i-Bu > s-Bu > t-Bu

SN2 Mechanism - X Groups

• larger leaving groups react faster
  I- > Br- > Cl- >> F-
• poor leaving groups
  (unstable anions, strong bases)
  OH- , RO- , NH2-

SN1 Mechanism

• two-step mechanism
  first X- leaves, then Nu- bonds
• carbocation intermediate
  R-X ----> R+ + X-
  R+ + Nu- ----> R-Nu
  

SN1 Mechanism - Evidence

• reaction rate proportional to concentration of RX reactant,
  but independent of concentration of Nu
  Rate = k [RX]
• kinetics are first-order
• mechanism is unimolecular

SN1 Mechanism - Evidence

• stereochemistry is scrambled
• chiral reactant gives racemic product
• carbocation intermediate is achiral

SN1 Mechanism - R Groups

• R groups that make more stable carbocations react faster
  3° > 2° > 1° > CH3
• tertiary RX react by SN1
• CH3 and primary RX react by SN2
• secondary RX react either way

SN1 Mechanism - X Groups

• same effects as for SN2
  I- > Br- > Cl- >> F-

Elimination Reactions

• another common reaction of alkyl halides,
  usually in competition with substitution
• base removes H+ as X- leaves
  base attacks H
  (nucleophile attacks C)
  

E2 Elimination Mechanism

• concerted (single-step)
• the H and X eliminated must be aligned anti to one another
• the breaking sigma bonds merge into overlapping p orbitals for the pi bond

E2 Stereochemistry

• anti periplanar arrangement of H and X may lead to specific products

E1 Elimination Mechanism

• two-step mechanism
  first X- leaves, then H+ leaves
• carbocation intermediate
• same first step as SN1

Substitution or Elimination?

• substitution: nucleophile attacks C
  either attacks RX [SN2] or R+ [SN1]
• elimination: base attacks H
  either attacks RX [E2] or R+ [E1]
  

Nucleophile or Base?

• most nucleophiles are also bases
  (and vice versa)
• to favor elimination:
  use a strong, hindered base
  e.g., KOtBu
• to favor substitution:
  use a small, unhindered nucleophile
  

Reactivity Patterns

• CH3X - can only do SN2
• primary (1°) RCH2X :
  SN2 works well, E2 with KOtBu
  SN1 and E1 don't work
• secondary (2°) R2CHX :
  SN2 works with a good nucleophile
  E2 works with KOtBu
  SN1 and E1 occur without strong base or nucleophile
• tertiary (3°) R3CX :
  SN1 works well with a good nucleophile
  E1 often competes with SN1
  E2 works well with KOtBu
  

Biological Substitutions

• methylating agents