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Nucleophilic Substitutions and Eliminations. Final CHEM 4A Review. Alkyl Halides React with Nucleophiles and Bases. Alkyl halides are polarized at the carbon-halide bond, making the carbon electrophilic

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alkyl halides react with nucleophiles and bases
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
the nature of substitution
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.
substitution mechanisms
Substitution Mechanisms
  • SN1
    • Two steps with carbocation intermediate
    • Occurs in 3°, allyl, benzyl
  • SN2
    • Two steps combine - without intermediate
    • Occurs in primary, secondary
reactant and transition state energy levels
Reactant and Transition-state Energy Levels

Higher reactant energy level (red curve) = faster reaction (smallerG‡).

Higher transition-state energy level (red curve) = slower reaction (largerG‡).

kinetics of nucleophilic substitution
Kinetics of Nucleophilic Substitution
  • Rate (V) is change in concentration with time
  • Depends on concentration(s), temperature, inherent nature of reaction (barrier on energy surface)
  • Arate law describes relationship between the concentration of reactants and conversion to products
  • A rate constant (k) is the proportionality factor between concentration and rate
reaction kinetics
Reaction Kinetics
  • The study of rates of reactions is called kinetics
  • Rates decrease as concentrations decrease but the rate constant does not
  • Rate units: [concentration]/time such as L/(mol x s)
  • The rate law is a result of the mechanism
  • The order of a reaction is sum of the exponents of the concentrations in the rate law – the example is second order
the s n 2 reaction
The SN2 Reaction
  • Reaction is with 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)
s n 2 process
SN2 Process
  • The reaction involves a transition state in which both reactants are together
s n 2 transition state
SN2 Transition State
  • The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups
characteristics of the s n 2 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 C=C (vinyl halides)

Characteristics of the SN2 Reaction
relative reactivity of nucleophiles
Relative Reactivity of Nucleophiles
  • Depends on reaction and conditions
  • More basic nucleophiles react faster
  • Better nucleophiles are lower in a column of the periodic table – more dispersed electron denisty
  • Anions are usually more reactive than neutrals
the leaving group
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
poor leaving groups
Poor Leaving Groups
  • If a group is very basic or very small, it is prevents reaction
the solvent
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
the s n 1 reaction
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
s n 1 energy diagram
SN1 Energy Diagram
  • Rate-determining step is formation of carbocation

Step through highest energy point is rate-limiting (k1 in forward direction)




V = k[RX]

stereochemistry of s n 1 reaction
Stereochemistry of SN1 Reaction
  • The planar intermediate leads to loss of chirality
    • A free carbocation is achiral
  • Product is racemic or has some inversion
s n 1 in reality
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
effects of ion pair formation
Effects 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
delocalized carbocations
Delocalized Carbocations
  • Delocalization of cationic charge enhances stability
  • Primary allyl is more stable than primary alkyl
  • Primary benzyl is more stable than allyl
characteristics of the s n 1 reaction
Characteristics of the SN1 Reaction
  • Tertiary alkyl halide is most reactive by this mechanism
    • Controlled by stability of carbocation
effect of leaving group on s n 1
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
nucleophiles in s n 1
Nucleophiles in SN1
  • Since nucleophilic addition occurs after formation of carbocation, reaction rate is not affected by a great degree by nature or concentration of nucleophile
solvent is critical in s n 1
Solvent Is Critical in SN1
  • Stabilizing carbocation also stabilizes associated transition state and controls rate

Solvation of a carbocation by water

effects of solvent on energies
Effects of Solvent on Energies
  • Polar solvent stabilizes transition state and intermediate more than reactant and product
alkyl halides elimination
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
zaitsev s rule for elimination reactions 1875
Zaitsev’s Rule for Elimination Reactions (1875)
  • In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates
mechanisms of elimination reactions
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
the e2 reaction mechanism
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
e2 reaction kinetics
E2 Reaction Kinetics
  • One step – rate law has base and alkyl halide
  • Transition state bears no resemblance to reactant or product
  • V=k[R-X][B]
  • Reaction goes faster with stronger base, better leaving group
geometry of elimination e2
Geometry of Elimination – E2
  • Antiperiplanar allows orbital overlap and minimizes steric interactions
e2 stereochemistry
E2 Stereochemistry
  • Overlap of the developing  orbital in the transition state requires periplanar geometry, anti arrangement

Allows orbital overlap

the e1 reaction
The E1 Reaction
  • Competes with SN1 and E2 at 3° centers
  • V = k [RX]
stereochemistry of e1 reactions
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
comparing e1 and e2
Comparing E1 and E2
  • Strong base is needed for E2 but not for E1
  • E2 is stereospecifc, E1 is not
  • E1 gives Zaitsev orientation
summary of reactivity s n 1 s n 2 e 1 e 2
Summary of Reactivity: SN1, SN2, E1, E2
  • Alkyl halides undergo different reactions in competition, depending on the reacting molecule and the conditions
  • Based on patterns, we can predict likely outcomes