Chapter 11, Part 1: Polar substitution reactions involving alkyl halides
Overview: The nature of alkyl halides and other groups with electrophilic sp3
hybridized C leads them to react with nucleophiles and bases
Two types of reactions covered in Ch 11, which often compete with each other:
1. Substitution:
CH3CH2Cl
+
Nu-
CH3CH2Nu
+
Cl-
+
B:-
CH2=CH2 +
HB
+ Cl-
2. Elimination:
CH3CH2Cl
Both are common in compounds where the sp3-carbon is bonded to an
electronegative atom
„
alkyl halides, alcohols, ethers
„
due to electronegativity of the halogen, C-X bond breaks easily: the
halogen is a good leaving group
Part 1: Substitution reactions
Two possible scenarios lead to substitution products:
„
A nucleophile is attracted to the polar C-X bond; as it approaches
and begins to bond with C, the C - X bond breaks and the halide ion
leaves
„
Under certain conditions, a weak C - X bond breaks to form a
carbocation. As X - leaves, a nucleophile is able to bond to the
carbocation
Which pathway actually occurs depends on several factors:
„
„
„
„
the nature of the nucleophile
the nature of the leaving group
the structure of the molecule at the sp3 carbon
reaction conditions
Scenario #1: A one-step reaction with the nucleophile = The SN2 reaction
SN2 = substitution, nucleophilic, bimolecular
The rate law for this process:
Rate = k [alkyl halide] [nucleophile]
Two key aspects of SN2 mechanism:
HO- +
CH3 – Br
HO – CH3 +
Br-
„
One step process (concerted)
„
Back-side attack of the nucleophile at the carbon produces an
inversion in stereochemistry at the carbon:
Four key factors that increase the likelihood of an SN2 type substitution:
1)
Easy access to the substrate (alkyl halide): 1o works best
„
The pathway occurs much more slowly for substituted (2o or 3o) alkyl halides
due to steric hindrance by the alkyl groups attached to the C
Reactivity:
methyl
> 1o RX
> 2o RX > 3o RX
2)
A strong attacking nucleophile
This is a key factor since rate depends on both R-X and Nu.
“Nucleophilicity” = ability of a nucleophile to speed up the reaction:
Factors influencing reactivity of the nucleophile:
A. Basicity: When comparing nucleophiles that have the same attacking atom,
the stronger the base, the better it is as a nucleophile
Base strength increases as pKa of conjugate acid increases
*NOTE: Acting as a base is NOT the same as acting as a nucleophile
B. Charge:
Negatively charged species are usually better nucleophiles than neutral
Some atoms (such as C) aren’t nucleophilic at all unless they are (-) charged
Basic reaction conditions can help keep nucleophile negatively charged
C. Size:
Within a group in the periodic table, the larger the size of the attacking
atom, the better the nucleophile, due to increased polarizability
Compare I- vs. Cl-; SH- vs. OH-
3)
A good “leaving group”
The better the leaving group, the faster an SN2 reaction occurs
Poor leaving groups raise the energy of the TS while good ones lower ΔG+
Example: for the halide ions, the weaker bases are better leaving groups:
Increasing basicity
For any R-X, reactivity by SN2 pathway: R-I
>
R-Br >
R-Cl
>
R-F
Good leaving groups:
I-, Br-, -OTos
So-so:
ClPoor leaving groups:
F-, OH-, NH2-, OR(Alcohols, ethers, amines do not react directly by the SN2 mechanism!)
4)
A solvent that doesn’t interfere with the process (aprotic is best)
Protic solvents:
Can donate a hydrogen in a hydrogen-bonding interaction
Examples: water, alcohols (CH3OH, CH3CH2OH)
They prevent the nucleophile from getting to its destination by solvation
Result: Slower reaction rate, particularly for normally “good” nucleophiles
Aprotic solvents:
Cannot donate a hydrogen in a hydrogen-bonding interaction and
therefore are not attracted to the nucleophilic species.
Examples: CH2Cl2, diethyl ether, THF, toluene, acetone
In aprotic solvents, the nucleophile is not affected; in fact the solvents help to
stabilize the transition state, thus lowering activation energy…SN2 reactions
can proceed more quickly in aprotic solvents!
Practical applications of the SN2 reaction:
A wide range of nucleophiles can react with alkyl halides, replacing the halide
with new functional groups and making substitution a versatile synthetic tool:
Alkynes:
CH3CH2 Br
Alcohols:
CH3CH2 Br
+ OH
CH3CH2 OH
Ethers:
CH3CH2 Br
+ OCH3
CH3CH2 OCH3
Amines:
CH3CH2 Br
+
NH3
CH3CH2 NH3Br
+
C C CH3
CH3CH2 C
C
CH3
+
+
Br-
Br+ Br-
O
O
+ C CH3
HO
CH3CH2 O C CH3 + Br-
Esters:
CH3CH2 Br
Nitriles:
CH3CH2 Br
Thiols:
CH3CH2 Br
+ SCH3
Coupling:
CH3CH2 Br
+
+
C N
RMgBr
CH3CH2 C
N
CH3CH2 SCH3
CH3CH2 R
+ Br+ Br-
+ MgBr 2
Intermolecular reactions (above examples) involve two separate molecules
Intramolecular SN2: If the alkyl halide also contains another nucleophilic group, it can
undergo an intramolecular reaction between the halide C and the Nu, forming a ring:
H
Br
NH2
N
H
Br-
Using SN2 reactions: Will reaction proceed spontaneously in the forward direction? Yes, if
„
The halide to be replaced is a better leaving group than the incoming group
„
This usually requires that the incoming group is a stronger nucleophile
„
If incoming and outgoing groups are nearly equal in basicity, reaction is
reversible; can be driven forward by removing product as it forms
(LeChatelier's principle)
Scenario #2: A two-step substitution reaction with a carbocation
intermediate = The SN1 reaction
ƒ A 3o R-X isn’t likely to react by SN2 pathway, but 3o alkyl halides do react
with bases to produce substitution products, and conc. of Nu has no effect
on rate
An alternate mechanism: SN1 = substitution, nucleophilic, unimolecular
rate = k [alkyl halide]
Two step reaction:
1) Slow step:
Loss of leaving group to form
carbocation intermediate
2) Faster step:
Reaction of carbocation
with nucleophile
CH 3
H 3C
A typical SN1
reaction
C
Br
C
CH3
o
3 alkyl halide
o
H 3C
CH 3
H 3C
H2O
+ Br-
C
HO
CH 3
3 carbocation
CH 3
CH 3
o
3 alcohol
What affects SN1 reactivity?
„
1o, 2o, 3o RX: Relative reactivity by SN1 depends on structure of carbocation
1o RX <
„
2o RX
Leaving group: How good is it at leaving?
<
3o RX
„
„
Strength of the nucleophile—doesn’t matter so much!
The ability of the solvent to stabilize the carbocation:
Protic solvents that hinder SN2 rxns
actually help SN1 rxns
Additional considerations when dealing with carbocation-based mechanisms:
1) Stereochemistry:
Recall stereochemistry of addition reactions: simple carbocations form racemic mixture:
Et
Ph
HBr
H
Ph
Et
Ph
C
Br-
CH 3
H
Et
C
Br
Ph
Et
C
+
H 3C
CH3
Br
SN1 reactions that produce a chiral center also give a racemic mixture of products
Et
Ph
C
Br
2)
Et
Ph
C
CH 3
+ Br-
CH 3
Et
Ph
H2O
C
HO
C
+
CH 3
Et
Ph
H3 C
OH
Resonance makes carbocations more stable, favors SN1 pathway
3) Carbocations are prone to rearrangement, may affect final product of SN1
Ex:
H 3C
CH
H 3C
H
C CH 3
Br
H 2O
SN1 mechanism
SN2 mechanism
So, a substitution product has formed… was it SN1 or SN2?
Both pathways are possible. Which one is favored? In a competition, the pathway which
occurs most rapidly will be favored. Some factors that may influence pathway
o
1. Structure of alkyl halide:
3
2
o
1
o
SN2
SN1
2. Concentration of nucleophile: Rate of SN1 pathway does not depend on [Nu]
Rate of SN2 = k [RX][Nu]
3. Reactivity of nucleophile: affects rate of SN2 but not rate of SN1
ƒ
SN2 pathway is favored by higher concentration and more reactive nucleophile.
ƒ
Conversely, low concentration or use of weaker nucleophile may favor SN1
4. Choice of solvent:
ƒ
SN1 reactions are favored by solvents capable of stabilizing a transition state that
closely resembles the (+)-charged carbocation intermediate - polar solvents best
ƒ SN2 reactions are favored by aprotic solvents and slowed down by protic solvents
Summary:
SN2 is favored by:
High conc. of strong nucleophile
A polar aprotic solvent
Less bulky & 1o R-X
SN1 is favored by:
A weaker nucleophile
A polar protic solvent
Substituted R-X that form stable
carbocations
Outcome of SN2:
Inversion of configuration
No rearrangement of C skeleton
Outcome of SN1:
Products are racemic mixtures
Rearrangements are likely
Some substitution reactions involving alkyl halides from Ch. 10 (Part 2)
The polarity of the C – X bond is key to understanding most RX reactions
1. Transforming alcohols to alkyl halides by polar substitution
Alkyl halides and alcohols have in common a polar bond between C and functional group:
R – CH2 – Br
R – CH2 – Cl
R – CH2 – OH
However, the OH group of alcohols is a poor leaving group compared to Br, Cl, or I
3o alcohols react readily with HCl, HBr or HI by SN1 mechanism to make 3o alkyl halides; this
works because they form a stable carbocation intermediate, but is unlikely with 1o or 2o ROH
CH 3
OH
HBr
ether
CH 3
Br
Preparation of 1o and 2o alkyl halides from alcohols by SN2 reaction:
•
•
1o & 2o alcohols require a bit more “encouragement” to get rid of the OH group
Halogenating reagents help “activate” the removal of the OH group
• These reagents reduce the risk of undesired elimination reactions.
• Reactions proceed with inversion
Some advantages to preparing alkyl halides from alcohols
•
The alcohols are often inexpensive and readily available
•
These reactions tend to produce only the desired major product, not mixtures like you
would get by radical halogenation
2. Organometallic Reagents:
Using metals to “activate” carbon towards SN2 substitution
ƒ Alkyl halides have a partial positive charge on the C bearing the halogen
ƒ Reaction of alkyl halides with certain metals results in “insertion” of metal
ƒ Produces a new carbon-metal bond in which the carbon now bears the
partial negative charge
ƒ Useful way to make the carbon nucleophilic
ƒ Earlier example: A nucleophilic C is generated in deprotonation of acetylene
to make acetylide ions – these then react with alkyl halide to form C-C bond
2A. Grignard Reagents:
•
•
•
Used to form new C – C bonds
Used in reactions with carbonyl compounds (more on this in CHM252)
Used in substitution reactions with alcohols to make ethers
Magnesium inserts itself into the C – X bond of 1o, 2o or 3o alkyl halides:
CH3 – Br
+
Mg
CH3 – Mg – Br
Dry ether
bromomethane
Methylmagnesium bromide
(a Grignard reagent)
Grignard reagents react readily with any electrophile which makes them useful, but
you can also get unwanted side reactions with any source of H+
Since they behave like bases, they react readily with H2O to replace X with H:
CH3CH2CH2-Mg-Br
H2O, H+
CH3CH2CH3 + MgBrOH
Note: The formation of a Grignard reagent can be considered an organic reduction since
the electron density on the carbon atom increases
Reduction:
increasing e- density on C by forming C – H , C – M (metal)
or by breaking C – O, C – N, or C – X
Reactions that form alkyl halides are considered oxidations
2B. Other organometallic reagents with nucleophilic C
Organolithium reagents
Lithium is small and strongly electropositive; makes the bonded carbon strongly basic
2 Li
CH3CH2CH2CH2-Br
CH3CH2CH2CH2–Li + LiBr
Pentane
•
•
•
The resulting organolithium reagents are very strong nucleophiles
Can be used in many of the same reactions as Grignard reagents
RLi reagents are used in the preparation of the Gilman reagent (below), which is a
milder form of the nucleophile
Gilman reagents:
Further reaction of RLi with copper produces: R2CuLi
ether
2 CH3CH2Li + CuI
(CH3CH2)2CuLi
+
LiI
2C: SN2 substitution: organometallic coupling reactions
Alkyl bromides, iodides & chlorides can react with Gilman reagents
(or Grignards) in a carbon-skeleton building reaction, by SN2 mechanism:
Ex:
H2 C
I
ether
+
H
(CH3CH2)2CuLi
0 oC
CH2 CH 2 CH 3
H
Choice of halogens in making & using alkyl halides in substitution rxns
•
Our focus has been primarily on alkyl bromides, chlorides & iodides because they
contain a good leaving group and are readily available commercially
•
Alkyl fluorides are not readily prepared by the same methods; for example, fluorine
radicals are extremely reactive & unpredictable so radical fluorination is impractical
•
Alkyl fluorides also are less useful as starting reagents; F is a poor leaving group and
thus not easily substituted out
Practice problems: Substitution of Alkyl Halides
For each reaction, predict the mechanism (SN1 or SN2) and the structure of the substitution
product(s). If stereoisomers are possible, indicate which ones are produced.
1 M Na+ -OCH2CH3
1) (R)-2-bromopentane
DMSO
2) (R)-2-bromopentane
CH3CH2OH
1 M Na+ -OCH3
3) trans-1-chloro-2-methylcyclohexane
DMSO
4) trans-1-chloro-2-methylcyclohexane CH3OH
5) 3-bromo-3-methylpentane
H2O
6) 3-bromo-3-methylpentane
-
7) bromocyclopentane
OH
Na+ -:C=C-CH2CH3
ether
8) bromocyclopentane
(CH3CH2)2CuLi
ether
Chapter 10 problems