CHP 8 Questions
8.
8.1-31, 33, 35, 40-42.
Nucleophilic Substitution Reactions
8.1
The General Reaction
In the reaction of chloromethane with hydroxide ion the hydroxide ion is substituted for
the chlorine group. The hydroxide ion is donating a pair of electrons to the carbon and is
termed a Nucleophile. The nucleophile is electron rich species that seeks an electron
deficient site. Nucleophiles are Lewis bases.
The carbon of the chloromethane is electron deficient and termed an Electrophile.
Electrophiles are Lewis acids. The carbon atom of chloromethane, electrophile, accepts a
pair of electrons from the hydroxide ion, nucleophile.
To avoid exceeding the proper valence of carbon, the chlorine atom departs with the
electron pair of the C-Cl bond. The chloride is termed the Leaving Group.
Example
The concept of nucleophiles and electrophiles is one of the most important concepts in
organic chemistry. This reaction is termed a nucleophilic substitution reaction since a
nucleophile replaces the leaving group. The general reaction can be depicted as
Nu:- + R-L
→
Nu-R + L:-
8.2
Reaction Mechanisms
A reaction mechanism shows the individual steps of a reaction – the order in which the
bonds are broken and formed. In a nucleophilic substitution reaction there are three
possible mechanisms: 1) the bond to the leaving group is broken first, followed by
formation of the bond with the nucleophile, 2) the bond to the nucleophile is formed first,
then the bond to the leaving group is broken, 3) the bond breaking and formation occur
simultaneously. Pathways 1 and 3 occur while pathway 2 does not since it would require
a pentavalent carbon. Examples:
8.3
Bimolecular Nucleophilic Substitution
Considering the reaction of hydroxide ion with chloroethane:
OH- + CH3CH2Cl
→
CH3CH2OH + Cl-
The rate of this reaction is dependent upon the concentration of hydroxide ion and
chloroethane. The reaction is second—order reaction where both EtCl and OH- are
involved with the rate determining step of the reaction.
Rate = k[EtCl][OH-]
This reaction is consistent with mechanism 3 above and is termed a second order
nucleophilic substitution reaction (SN2). The reaction coordinate diagram for this
reaction involves a single transition state.
8.4
Stereochemistry of the SN2 Reaction
Substitution reactions that occur on a chiral carbon can have three possible outcomes.
The sterocenter can be retained, inverted or racemized. Figure 8.2
Reactions that occur via an SN2 reaction occur with inversion of the stereocenter. The
incoming nucleophile approaches the carbon from the opposite side of the leaving group.
At the transition state the carbon has a trigonal planar geometry and is sp2 hybridized.
The leaving group departs as the nucleophile carbon bond is fully formed. Figure 8.3
8.5
Effect of Substituents on the Rate of the SN2 Reaction
The rate of the SN2 reaction decreases moving from methyl chloride to ethyl chloride (a
1o alkyl halide) to isopropyl chloride (2o) to tert-butyl chloride (3o). The relative rates are
listed in Table 8.1:
MeCl
30
EtCl
1
iPrCl
0.025
t-Bu
0
This is explained by increases in the energy of the transition state due to steric
interactions between the alkyl substituents and the incoming nucleophile. Fig 8.4
One can observe the increased steric constraints of the different alkyl chlorides via space
filling models. Fig 8.5
While the most important differences in the rate of SN2 reactions depend upon the
structure of the electrophilic carbon (methyl, 1o, 2o, or 3o). There are exceptions to this
rule. Neopentyl chloride, a 1o alkyl chloride, reacts 2500 times slower than isopropyl
chloride. This is due to the large steric bulk of the t-butyl substituent of neopentyl
chloride. Both allyl chloride and benzyl chloride react much faster than ethyl chloride.
This is due to the resonance stabilization of the transition state. Example
8.6
Unimolecular Nucelophilic Substitution
If we consider the reaction of acetate ion with tert-butyl chloride:
CH3CO2- + (CH3)3CCl
→
(CH3)3CO2CCH3 + Cl-
The reaction looks similar to that of hydroxide ion with methyl chloride. However, the
rate of this reaction is only dependent upon the concentration of the tert-butyl chloride.
Rate = k[t-BuCl]
This indicates that only t-BuCl is present at the rate limiting transition state. The reaction
is termed a unimolecular nucleophilic substitution or (SN1) reaction. The reaction
mechanism has two steps. The first step is the unimolecular dissociation of the t-BuCl to
form a reactive intermediate (the t-Bu cation) followed by rapid reaction with the
nucelophile. This can be indicated by the reaction coordinate diagram in Figure 8.6.
Upon dissociation of the chloride ion a reactive intermediate is formed. This reactive
intermediate is a high energy, reactive species. But a local energy minimum. In the SN1
reaction the intermediate is a carbocation. The cationic carbon has only 6 electrons and is
sp2 hybridized. The transition state for conversion of the t-BuCl to t-Bu+ and Cl- has
structural characteristics similar to both the starting material and the intermediate. (EX)
Hammond’s Postulate states that the structure of the transition state is closer to that of the
species to which it is closer in energy. Fig 8.7
8.7
Effect of substituents on the rate of the SN1 reactions.
Methyl and primary alkyl chlorides do not undergo SN1 reactions. They only undergo
SN2. The formation of the carbocation is the rate limiting step of the reaction and the
stability of the carbocations follows the following order: 3o>2o>1o>Me. The substitution
of an alkyl group for a hydrogen results in significant stabilization of the carbocation.
This is due to overlap of the adjacent sigma bond which provides electronic
delocalization via hyperconjugation. Example.
Resonance stabilization of adjacent π-Bonds provides significant increases in the rates of
SN1 reactions. Example
//INSERT 8.8 to 8.12//
8.12 Competition between SN1 and SN2 Reactions
SN1 Reactions are favored by:
1) Stabilized carbocations (3o or resonance stabilized are best, 2o is ok)
2) Polar solvent
3) Poor nucleophiles are preferred.
SN2 Reactions are favored by:
1) Unhindered electrophilic carbon (Me and 1o excellent, 2o is ok)
2) Polar aprotic solvent.
3) Strong Nucleophiles are preferred.
8.13 Intramolecular Reactions
When a molecule contains both a nucleophile and an electrophile one can observe
intramolecular reactions. For reactions which generate 5 and 6 membered rings the reaction
can occur much more rapidly than the intermolecular reaction (> 103). This is primarily due
to the close proximity of the nucleophile and electrophile – lower entropic cost, and lack of
ring strain – no unfavorable enthalpy. Example
8.14 Competing Reactions
In addition to SN1 and SN2 reactions, other reactions can occur in competition. Elimination
reactions (CHP 9) occur when the leaving group and a hydrogen are lost from adjacent
carbons, resulting in the formation of a double bond. Figure 8.11
Another side reaction that can occur in SN1 reactions is the 1,2-hydride (or alkyl) shift. This
usually occurs when a carbocation is generated adjacent to a potentially more stable
carbocation. Typically this is a change from a secondary carbocation to a tertiary
carbocation. Example
It is also important to understand that allylic carbocations provide more than one site for
nucleophilic attack. Example