CHM 247 CH.11
Reactions ofAlkyl Halides: Nucleophilic Substitutions and Eliminations
• Carbon-halogen bond in an alkyl halide is polar and the carbon atom is electron-poor.
Thus alkyl halides are electrophiles.
• Alkyl halides do one of two things when they react with a nucleotide/base, such as
hydroxide ion: either they undergo substitution of the X group by the nucleophile, or they
undergo elimination of HX to yield an alkene.
11.1 The Discovery of Nucleophilic Substitution Reactions
• German chemist Paul Walden found that pure enantiomers of malic acid could be
introvconverted through a series of simple substitution reactions.
• Because (-)-malic acid was converted to (+)-malic acid, some reactions in the cycle must
have occureed with a change, or inversion, in configuration at the chirality centre.
• Nucleophilic substitution reaction: A reaction in which one nucleophile replaces another
attached to a saturated carbon.
• The inversion of stereochemical configuration must therefore take place in step 2, the
nucleophilic substitution of tosylate ion by acetate ion.
• From this and other similar reactions, workers concluded that the nucleophilic
substitution reaction of a primary or secondary alkyl halide or tosylate always proceeds
with inversion of configuration.
11.2 The S N Reaction
• Kinetics: referring to reaction rates. Kinetic measurements are useful for helping to
determine reaction mechanisms.
• Direct relationship between the rate at which the reaction occurs and the concentrations
of the reactants.
• Second-order reaction: A reaction whose rate limiting step is bimolecular and whose
kinetics are therefore dependent on the concentration of two reactants.
• S N reaction: A bimolecular nucleophilic substitution reaction. • SN2 is short for substitution, nucleophilic, bimolecular.An essential feature of anNS 2
mechanism is that it takes place in a single step without intermediates when the incoming
nucleophile reacts with the alkyl halide or tosylate from a direction opposite the group
that is displaced.
11.3 Characteristics of the S 2 Reaction
• The rate of a chemical reaction is determined by the activation energyΔG‡, the energy
difference between reactant ground state and transition state.
• Achange in conditions can affect the activation energy either by changing the reactant
energy level or by changing the transition-state energy level.
• Lowering the reactant energy or raising the transition-state energy increases the activation
energy and decreases the reaction rate; raising the reactant energy or decreasing the
transition-state energy decreases the activation energy and increases the reaction rate.
The Substrate: Steric Effects in the N 2
• The first N 2 reaction variable to look at it the structure of the substrate.A hindered
substrate should prevent easy approach of the nucleophile, making bond formation
difficult. The transition state for a sterically hindered substrate is higher in energy and
forms more slowly than the corresponding transition state for a less hindered substrate.
• Vinylic halides and aryl halides are not shown on this reactivity because they are
unreactive towards S 2 displacement.
The Nucleophile • The nature of the nucleophile has a major effect on the S 2Nreaction.Any species that it
neutral or negatively charged can act as a nucleophile (as long as it has an unpaired set of
electrons and is a lewis base).
• If the nucleophile is negatively charged, the product is neutral; if the nucleophile is
neutral, the product is positively charged.
• Reactivity of a given nucleophile can change from one reaction to another.
• Nucleophile strength: Nucleophilicity roughly parallels basicity. Nucleophilicity usually
increases going down a column of the periodic table. I > Br > Cl. Negatively charged
nucleophiles are usually more reactive than neutral ones.
The Leaving Group
• Another variable that can affect the S N reaction is the nature of the group displaced by
the incoming nucleophile. The leaving group is expelled with a negative charge in most
S 2 reactions, so the best leaving groups are those that best stabilize the negative charge
in the transition state.
• The greater the extent of charge stabilization by the leaving group, the lower the energy
of the transition state and the more rapid the reaction.
• Weak bases makes good leaving groups.
• Weak bases such as Cl, and Br and tosylate ions make good leaving groups.
• Alkyl fluorides, alcohols, ethers, and amines do not typically undergo S 2 Neactions.
• Converting an alcohol to a better leaving group is a good leaving group will allow a
reaction to occur.
• Ethers don’t typically undergo S 2Nreactions, but epoxides, due to angle strain, are much
more reactive than other ethers. •
• Rates strongly affected by the solvent. Protic solvents ( -OH or –NH) are generally worst
for SN2 reactions while polar aprotic solvents are the best.
• Protic solvent: A solvent such as water or alcohol that can act as a proton donor.
• Solvation: The clustering of solvent molecules around a solute particle to stabilize it.
• Protic solvents slow down the reaction by salvation of the reactant nucleophile. The
solvent molecules hydrogen bind the nucleophile and form a cage around it.
• Polar aprotic solvents increase the rate of N 2 reactions by raising the ground-state energy
of the nucleophile.
ASummary of S 2 RNaction Characteristics
• Substrate: Steric hindrance raises the energy of the N 2 transition state, increasing the
activation energy and decreasing the reaction rate.As a result, N 2 reactions are best for
methyl and primary substrates. Secondary substrates react slowly, and tertiary substrates
do not react by an SN2 mechanism.
• Nucleophile: Basic, negatively charged nucleophiles are less stable and have a higher
ground-state energy than neutral ones, decreasing the activation energy and increasing the
S N reaction rate.
• Leaving group: Good leaving groups (more stable