Transcript Chapter 8 Lecture

Nucleophilic Substitution
Nucleophilic Substitution
–
Y:
+
R
X
Y
R +
–
:X
Nucleophile is a Lewis base (electron-pair donor),
often negatively charged and used as
Na+ or K+ salt.
Substrate is usually an alkyl halide.
Effect of Hybridization of the Carbon
Halogens connected to sp2 carbons are not reactive
under the conditions discussed in this chapter.
sp3 carbon
reactive
sp2 carbons
not reactive
Nucleophilic Substitution
Therefore, substrate cannot be an a
vinylic halide or an aryl halide, except under
certain conditions to be discussed in
Chapter 12.
Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile
R'
..–
O:
..
+
R
X
gives an ether
R'
..
O
..
R
+
:X
–
Example
(CH3)2CHCH2ONa + CH3CH2Br
Isobutyl alcohol
(CH3)2CHCH2OCH2CH3 + NaBr
Ethyl isobutyl ether (66%)
Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile
O
..–
+
R
X
R'C O:
..
gives an ester
O
R'C
..
O
..
R
+
:X
–
Example
O
CH3(CH2)16C
OK
+
CH3CH2I
acetone, water
O
CH3(CH2)16C
O
CH2CH3 +
Ethyl octadecanoate (95%)
KI
Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile
H
..–
S:
..
H
..
S
..
+
R
X
gives a thiol
R
+
:X
–
Example
KSH + CH3CH(CH2)6CH3
Br
ethanol, water
CH3CH(CH2)6CH3 + KBr
SH
2-Nonanethiol (74%)
Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile
:N
–
C:
+
C
R
R
X
gives a nitrile
:N
+
:X
–
Example
NaCN
+
Br
DMSO
CN
+
NaBr
Cyclopentyl cyanide (70%)
Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile
–
:N
..
–
:
N
..
+
gives an alkyl azide
+
–
:N N N
..
..
R
+
N
R
+
X
:X
–
Example
NaN3 + CH3CH2CH2CH2CH2I
2-Propanol-water
CH3CH2CH2CH2CH2N3 + NaI
Pentyl azide (52%)
Table 8.1 Examples of Nucleophilic Substitution
Iodide ion as the nucleophile
..–
: ..I:
+
R
X
gives an alkyl iodide
..
: ..I
R
+
:X
–
Example
CH3CHCH3 + NaI
Br
acetone
CH3CHCH3 + NaBr
I
63%
NaI is soluble in acetone;
NaCl and NaBr are not
soluble in acetone.
Relative Reactivity of Halide Leaving Group
Alkyl iodides are most reactive since:
(a) the carbon-iodine bond is weakest for the halogens;
(b) iodide is the weakest base of the halides (this implies
that iodide is most stable) since HI is the strongest acid.
SN2 Mechanism of Nucleophilic Substitution
Since the rate of reaction depends on the halide the rate
determining step must involve breaking of the carbonhalogen bond.
Kinetic studies of the above reaction showed that the
rate is also dependent on the hydroxide concentration:
The rate determining step therefore involves both the
nucleophile and the alkyl halide.
SN2 Mechanism of Nucleophilic Substitution
Overall reaction.
The mechanism (one step).
The transition state.
The configuration at carbon.
From
Potential Energy Diagram for SN2 Reaction
Inversion of Stereochemistry with SN2
The nucleophile attacks carbon from the side opposite
the bond to the leaving group. The SN2 reaction at a
chirality center proceeds with inversion of configuration
at the carbon bearing the leaving group.
Inversion of Configuration
The reaction of (S)-2-bromooctane proceeds with
inversion of configuration as shown in the equation:
The transition state is:
Steric Effects and SN2 Reaction
Rates
Effect of the Alkyl Group on the Rate
The rate of the reaction:
RBr + LiI 
RI + LiBr
decreases with increasing steric hindrance.The reaction
is fastest with the least hindered methylbromide.
The rate of SN2 reactions normally decreases in the order:
CH3X > primary > secondary > tertiary
Effect of b-Substitution on the Rate
Substitution on the b-carbon also slows reaction
by adding steric hindrance to the carbon bearing
the halogen.
Neopentyl bromide (a primary
alkyl halide) is so hindered that
it is essentially unreactive.
Nucleophiles and Nucleophilicity
Neutral Nucleophiles
Not all nucleophiles are negatively charged. Amines
(R3N), sulfides (R2S) and phosphines (R3P) are good
neutral nucleophiles.
Neutral Nucleophiles
Solvolysis reactions with water (hydrolysis) and alcohols
also involve neutral nucleophiles
SN2 hydrolysis reaction mechanism:
Nucleophilic Strength
Nucleophilicity (nucleophile strength) is a measure of
how fast a Lewis base displaces a halogen in a reaction.
The table compares rates of reaction with CH3I in CH3OH.
Nucleophilicity
When comparing nucleophiles with the same nucleophilic
atom then the stronger base is the stronger nucleophile.
The stronger base is the conjugate base of the weaker
acid.
This generalization holds when comparing nucleophiles
in the same row of the Periodic table
Nucleophilic Strength
When comparing nucleophiles that have the same
nucleophilic atom the charged nucleophile is stronger.
Nucleophilic Strength
When comparing nucleophiles in the same group of
the Periodic Table the most important factor is solvation
of the nucleophile.
Iodide is the weakest base of the halogens but the best
nucleophile. The smaller chloride is a stronger base but
is more solvated because it has higher charge density.
The SN1 Mechanism of
Nucleophilic Substitution
A question...
Tertiary alkyl halides are very unreactive in
substitutions that proceed by the SN2 mechanism.
Do they undergo nucleophilic substitution at all?
Yes. But by a mechanism different from SN2.
The most common examples are seen in
solvolysis reactions.
Nucleophilic Substitution of Tertiary Alkyl halides
The reaction
(CH3)3CBr + 2 H2O  (CH3)3COH + H3O+ + Br-
follows a first order rate law:
Rate = k[(CH3)3CBr]
And the reaction is termed SN1.
SN1 Mechanism of Nucleophilic Substitution
Step 1: Ionization to form a tertiary cation.
Step 2: Addition of a water molecule.
Step 3: Deprotonation.
Potential Energy Graph of the SN1 Reaction
Characteristics of the SN1 mechanism
first order kinetics: rate = k[RX]
unimolecular rate-determining step
carbocation intermediate
rate follows carbocation stability
rearrangements sometimes observed
reaction is not stereospecific
much racemization in reactions of
optically active alkyl halides
The Alkyl Halide and the Rate of SN1 Reaction
Comparison of a series of alkyl bromides under SN1
reaction conditions (solvolysis) reveals that tertiary alkyl
halides react fastest.
In general, methyl and primary alkyl halides never
react by the SN1 mechanism and tertiary alkyl halides
never react by SN2.
Stereochemistry of the SN1 Reaction
SN1 reactions proceed through the carbocation which is
planar.
The nucleophile can react from either side however,
surprisingly a 1:1 mixture of products is not always formed.
Stereochemistry of the SN1 Reaction
The incomplete loss of stereochemistry is explained by a
partial shielding of one side of the cation by the halide
leaving group.
Carbocation Rearrangements in SN1 Reactions
Rearrangements are evidence for carbocation
intermediates and serve to confirm the SN1 reaction
mechanism.
Mechanism with Rearrangement
Step 1: Ionization.
Step 2: H-shift (to form a more stable tertiary cation).
Step 3: Water addition to the carbocation.
Step 4: Deprotonation.
Effect of Solvent on Substitution
Solvent affects the rate of a reaction not the products
formed and the questions are:
1. What properties of the solvent influence the rate most?
2. How does the rate-determining step of the mechanism
respond to the properties of the solvent?
Classification of Solvents
Protic solvents are those that are capable of hydrogen
bonding. Normally they have an –OH group or an N-H
group.
Aprotic solvents are not hydrogen bond donors.
Polarity of a solvent is related to its dielectric constant (e).
Solvents with high dielectric constants are considered
polar and those with low dielectric constants are non polar.
Properties of Solvents
Solvents and SN2 Reactions
Polar protic solvents hydrogen bond to, and solvate, the
nucleophile and suppress its nucleophilicity and reduce
the rate of reaction.
Polar aprotic solvents cannot solvate the nucleophile
and the nucleophile is free to react.
Solvents and SN2 Reactions
The table below shows the effect of solvent on this reaction.
The reaction is much faster in polar aprotic solvents.
Solvents and SN2 Reactions
This reaction was studied under two different conditions.
Reaction of hexyl bromide in a polar protic solvent required
heating for 24 hours to form 76% of hexyl cyanide.
With a polar aprotic solvent dimethyl sulfoxide and the less
reactive hexyl chloride at room temperature for 20 minutes
yielded 91 % of hexyl cyanide.
Solvents and SN1 Reactions
Comparison of the rates of solvolysis of (CH3)3CCl and
dielectric constant of the solvent shows faster reaction
with more polar protic solvent.
The reaction is much faster in more polar protic solvents.
Solvents and SN1 Reactions
The transition state for formation of the carbocation and
the halide anion is lowered in a more polar solvent.
When...
Primary alkyl halides undergo nucleophilic
substitution: they always react by the SN2
mechanism.
Tertiary alkyl halides undergo nucleophilic
substitution: they always react by the SN1
mechanism.
Secondary alkyl halides undergo nucleophilic
substitution: they react by the
SN1 mechanism in the presence of a weak
nucleophile (solvolysis).
SN2 mechanism in the presence of a good
nucleophile.
Substitution and Elimination as
Competing Reactions
Substitution and/or Elimination
Lewis bases can react as nucleophiles or bases resulting
in substitution or elimination.
Substitution and/or Elimination
Examples where both substitution and elimination
products are formed:
The competition between substitution and elimination is:
Steric Effect on the SN2/E2 Reactions
The balance between substitution and elimination can
be affected by changing from an unhindered base to a
more hindered base.
Unhindered base (CH3CH2ONa): predominantly substitution.
Hindered base (CH3)3COK: predominantly elimination
Basicity and Substitution
Nucleophiles that are weak bases tend to give higher
ratios of substitution. Azide (N3-) and cyanide (CN-)
are weak bases.
Nucleophiles and Tertiary Alkyl Halides
Tertiary alkyl halides are very hindered and yield mixtures
of substitution and elimination by SN1 and E1 mechanisms
with neutral nucleophiles.
Addition of stronger bases results in elimination
exclusively through an E2 reaction.
Nucleophilic Substitution of
Alkyl Sulfonates
Nucleophilic Substitution of Sulfonates
Sulfonic acids are very strong acids similar to sulfuric acid.
Alkyl sulfonates (ROTs) are prepared by reaction of
alcohols with a sulfonyl chloride:
Nucleophilic Substitution of Sulfonates
Sulfonates are stable anions and very weak bases
because they are the conjugate bases of very strong acids.
Sulfonates are therefore excellent leaving groups.
Hydroxide (HO-) is a very poor leaving group so transforming
an alcohol into a sulfonate generates a good leaving group.
Nucleophilic Substitution of Sulfonates
Alkyl sulfonates react faster than iodides.
Nucleophilic Substitution of Sulfonates
Sulfonates are better leaving groups than halides so they
can be used to form alkyl halides by substitution.
Nucleophilic Substitution of Sulfonates
The formation of a tosylate does not change the
configuration of the alcohol so an optically pure alcohol
is transformed into an enantiopure tosylate.
Nucleophilic Substitution of Sulfonates
Secondary tosylates also undergo elimination with strong
bases.
Secondary tosylates undergo substitution with weak
bases.
Nucleophilic Substitution and
Retrosynthetic Analysis
Retrosynthetic Analysis
Retrosynthetic analysis works back from the target
molecule. Here nucleophilic substitution reaction can
form the thiol.
Leaving group X could be a tosylate made from an alcohol.
The alcohol could be made from an alkene.
Retrosynthetic Analysis to Synthesis
The full retrosynthetic analysis is:
Once the retrosynthetic analysis has been developed
simply write the synthesis starting from the alkene.
Anti-Markovnikov
addition of H-OH