CHAPTER 6 Properties and Reactions of Haloalkanes: Bimolecular Nucleophilic Substitution

1
CHAPTER 6Properties and Reactions of
Haloalkanes Bimolecular Nucleophilic
Substitution
2
Physical Properties of Haloalkanes
6-1
The bond strength of C-X decreases as the size of
X increases. A halogen uses a p orbital to
overlap an sp2 orbital on a carbon atom. As the
size of the halogen p orbital increases (F lt Cl lt
Br lt I), the percentage overlap with the smaller
sp2 carbon orbital is less and the bond strength
decreases.
3
The C-X bond is polarized. Because halogens are
more electronegative that carbon, carbon-halogen
bonds are polarized. The halogen atom possesses
a partial negative (d-) and the carbon atom a
partial positive (d) charge.
The electrophilic d carbon atom is subject to
attack by anions and other nucleophilic
species. Cations and other electron-deficient
species attack the halogen atom.
4
Haloalkanes have higher boiling points than the
corresponding alkanes. Boiling points of
haloalkanes are higher than those of the parent
ankanes mainly due to dipole-dipole interactions
between the haloalkane molecules
As the size of the halogen increases there are
also larger London forces between the haloalkane
molecules. Larger atoms are more polarizable and
interact more strongly through London forces.
5
Nucleophilic Substitution
6-2
Haloalkanes can react with nucleophiles at their
electrophilic carbon atom. The mucleophile can be
charged, as in OH- or neutral, as in NH3. In
nucleophilic substitution of haloalkanes, the
nucleophile replaces the halogen atom.
6
Nucleophilic Substitution
6-2
Nucleophiles attack electrophillic
centers. Nucleophilic substitution of a
haloalkane can be described by two general
equations
In both cases, the leaving group is the halide
anion, X-. In describing reactions, the organic
starting material is called the substrate of the
reaction. Here, the substrate is being attacked
by a nucleophile.
7
Nucleophililc substitution exhibits considerable
diversity.
Rxn 1 OH- (KOH) displaces Cl- to produce an
alcohol. Rxn 2 OCH3- displaces Cl- to produce
an ether. Rxn 3 I- displaces Cl- to produce a
different haloalkane. Rxn 4 CN- (NaCN)
displaces Cl- to form a new C-C bond.
8
Rxn 5 The S analog of Rxn 2 forming a
thioether. Rxn 6 Neutral NH3 produces a
cationic ammonium salt Rxn 7 Neutral PH3
produces a cationic phosphonium salt.
9
Halides can serve as nucleophiles and as leaving
groups in nucleophilic substitution reactions.
These reactions are reversible. Strong bases,
such as HO- and CH3O-, however do not serve as
good leaving groups. Substitution reactions
involving these species are not reversible.
10
Reaction Mechanisms Involving Polar Functional
Groups Using Electron-Pushing Arrows
6-3
Curved arrows depict the movement of electrons.
The oxygen lone pair of electrons ends up being
shared between the oxygen and the hydrogen. The
bonding pair electrons in the HCl molecule ends
up as a lone pair on the chloride ion.
11
Mechanisms in organic chemistry are described by
curved electron pushing arrows.
Notice that in the 1st and 3rd examples, the
destination of the moving electrons is a carbon
atom with a filled outer shell. In these
nucleophilic substitution and addition reactions,
room must be made in the outer shell of the
carbon atom to put the incoming electrons.
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A Closer Look at the Nucleophilic Substitution
Mechanism Kinetics
6-4
Consider the reaction between chloromethane and
sodium hydroxide
This experimental data showing the reactants,
products, and reaction conditions, gives no
information on how the chemical reaction occurred
or how fast it occurred. By measuring the rate
product formation beginning with several
different sets of reactant concentrations, a rate
equation or rate law can be determined.
13
A Closer Look at the Nucleophilic Substitution
Mechanism Kinetics
6-4
The reaction of chloromethane with sodium
hydroxide is bimolecular. The rate of a reaction
can be measured by observing the appearance of
one of the products, or by the disappearance of
one of the reactants. In the case of reaction
between chloromethane and hydroxide ion doubling
the hydroxide concentration (keeping the
chloromethane concentration fixed) doubles the
reaction rate. doubling the chloromethane
concentration (keeping the hydroxide
concentration fixed) also doubles the
reaction. These observations are consistent with
a second-order process whose rate law is Rate
kCH3ClHO- mol L-1 s-1.
14
All of the nucleophilic substitution reactions
show earlier follow this rate law (with different
values of k). The mechanism consistent with a
second order rate law involves the interaction of
both reactants in a single step (a
collision). Two molecules interacting in a single
step is call a bimolecular process. Bimolecular
nucleophilic substitution reactions are
abbreviated SN2.
15
Bimolecular nucleophilic substitution is a
concerted, on-step process. A SN2 substitution is
a one step process. The bond formation between
the nucleophile and the carbon atom occurs at the
same time that the bond between the carbon atom
and the electrophile is breaking. This is an
example of a concerted reaction.
16
There are two distinct stereochemical
alternatives for an SN2 concerted reaction
frontside displacement and backside displacement
In SN2 nucleophilic substitution reactions, the
transition state of the reaction is simply the
geometric arrangement of reactants and products
as they pass through the point of highest energy
in the single-step process.
17
Frontside or Backside Attack? Seterochemistry of
the SN2 Reaction
6-5
The SN2 reaction is stereospecific. When
(S)-2-bromobutane reacts with iodide ion, there
are two possible theoretical products Frontside
displacement the stereochemistry at C2 is
retained. The product is (S)-2-iodobutane. Backsi
de displacement the stereochemistry at C2 is
inverted. The product is (R)-2-iodobutane. Only
(R)-2-iodobutane is observed as a product. All
SN2 proceed with inversion of configuration.
18
A process in which each stereoisomer of the
starting material is transformed into a specific
stereoisomer of product is called
stereospecific. The same reaction shown with
Spartan molecular models and with electrostatic
potential maps is
19
The transition state of the SN2 reaction can be
described in an orbital picture.
Halfway through the course of an SN2 reaction,
the sp3 hybridization of the carbon atom has
changed to the planar sp2 hybridization
(transition state). As the reaction proceeds to
completion the carbon atom returns to the
tetrahedral sp3 hybridization.
20
Consequences of Inversion in SN2 Reactions
6-6
We can synthesize a specific enantiomer by using
SN2 reactions. When (R)-2-Bromooctane is reacted
with HS-, only (S)-2-octanethiol is obtained
If we had started with the S enantiomer of
2-bromooctane, only the R enantiomer of
2-octanethiol would have been produced.
21
In order to retain the R configuration of the
starting 2-bromooctane, a sequence of two SN2
reactions is used
The double inversion sequence of two SN2
processes results in a net retention of
configuration.
22
When a substrate contains more than one
stereocenter, inversion takes place only at the
stereocenter being attacked by the nucleophile.
Note that in the first case a meso product is
formed.
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Structure and SN2 Reactivity The Leaving Group
6-7

• The rates of SN2 reactions depend upon
• Nature of the leaving group.
• Reactivity of the nucleophile
• Structure of the alkyl portion of the substrate.
• Leaving-group ability is a measure of the ease of
  displacement.
• The leaving group ability of a leaving group can
  be correlated to its ability to accommodate a
  negative charge.
• For halogens, iodide is a good leaving group,
  while fluoride is a poor leaving group in SN2
  reactions. SN2 reactions of fluoroalkanes are
  rarely observed.
• Leaving-Group Ability
• (best) I- gt Br- gt Cl- gt F- (worst)

24
Other good leaving groups that can be displaced
by nucleophiles in SN2 reactions are
25
Weak bases are good leaving groups. Leaving group
ability is inversely related to base
strength. Weak bases are best able to accommodate
negative charge and are the best leaving groups.
(Weak bases are the conjugate bases of strong
acids.)
Note the sequence I- gt Br- gt Cl- gt F-
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Structure and SN2 Reactivity The Nucleophile
6-8

• Nucleophilicity of the nucleophile depends upon
• Charge
• Basicity
• Solvent
• Polarizability
• Nature of substituents

27
Increasing negative charge increases
nucliophilicity. Consider these experiments
Conclusion Comparing nucleophiles having the
same reactive atom, the species with the negative
charge is the more powerful nucleophile. A base
is always more nucleophilic than its conjugate
acid.
28
Nucleophilicity decreases to the right in the
periodic table. Consider these experiments
Conclusion Nucleophilicy correlates with
basicity. As we proceed from left to right across
the periodic table, nucleophilicity
decreases. (best) H2N- gt HO- gt NH3 gt F- gt H2O
(worst nucleophile)
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Should basicity and nucleophilicity be
correlated? Basicity is a thermodynamic property
Nucleophilicity is a kinetic phenomenon
Despite this difference in definition, there is a
good correlation between nucleophilicy and
basicity in the cases of charged versus neutral
nucleophiles along a row in the periodic table.
30
Solvation impedes nucleophilicity. Consider these
experiments
Conclusion Nucleophilicity increases in the
progression down a column of the periodic table
which is opposite the trend predicted by the
basicity of the nucleophiles tested.
31
When a solid dissolves in a polar solvent the
molecules or ions are surrounded by solvent
molecules and are said to be solvated. Generally
solvation weakens a nucleophile by forming a
shell of solvent molecules around the nucleophile
which impedes its ability to attack an
electrophile. Smaller ions are more tightly
solvated in a polar solvent than larger ones,
thus F- is much more heavily solvated than in I-.
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Protic and aprotic solvents the effect of
hydrogen bonding. Protic solvents are those
containing a hydrogen atom attached to an
electronegative atom and are capable of hydrogen
bonding.
Aprotic solvents lack positively polarized
hydrogen atoms and are also often used in SN2
reactions
33
Because aprotic solvents do not form hydrogen
bonds, they solvate anionic nucleophiles
relatively weakly. This results in an increase in
the nucleophiles reactivity. Bromomethane reacts
with KI 500 times faster in propanone than in
methanol. Consider the reaction of iodomethane
with chloride
The rate of the reaction is more than 106 times
greater in the aprotic solvent DMF than in
methanol.
34
Switching to an aprotic solvent increases the
reactivity of all anions, however the effect is
the largest for the smallest anion. The
differences in nucleophilic reactivity between
the halides are substantially reduced in aprotic
solvents, and can sometimes even be reversed.
35
Increasing polarizability improves nucleophilic
power. The degree of nucleophilicity increases
down the periodic table, even for uncharged
nucleophiles, for which the solvent effects would
be much weaker. H2Se gt H2S gt H2O, and PH3 gt NH3
This effect is due to the larger polarizability
of the larger atom at the bottom of the periodic
table The larger electron clouds allow for more
effective overlap in the SN2 transition state.
36
Sterically hindered nucleophiles are poorer
reagents. Nucleophiles having large bulky
substituents are not as reactive as unhindered
nucleophiles
Sterically bulky nucleophiles react more slowly.
37
Nucleophilic substitutions may be
reversible. Halide ions (except F-) are both good
nucleophiles and good leaving groups. The SN2
reactions of these halides are reversible.
The solubility of the sodium halides dramatically
decreases in the order NaI gt NaBr gt NaCl. NaCl
is virtually insoluble in propanone so reactions
involving the displacment of Cl- can be made go
to completion by using the sodium salt of the
attacking nucleophile
38
When the nucleophile in a SN2 reaction is a
strong base (HO-, CH3O-, etc.) it becomes a very
poor leaving group, and SN2 reactions involving
strong bases as nucleophiles are essentially
irreversible.
39
The relative reaction rate of iodomethane with a
variety of nucleophiles illustrates the previous
points
40
Structure and SN2 Reactivity The Substrate
6-9
Branching at the reacting carbon decreases the
rate of the SN2 reaction. The effects of
substituents on the reacting carbon can be seen
in the following data
41
The transition states of the reaction of OH- with
methyl, primary, secondary and tertiary carbon
centers explain the decrease in activity
The steric hindrance caused by adding successive
methyl groups to the electrophilic carbon
decreases the transition state stability to the
point that substitution at a tertiary carbon does
not occur at all. (fast) Methyl gt primary gt
secondary gt tertiary (does not occur)
(very slow)
42
Lengthening the chain by one or two carbons
reduces SN2 reactivity. Replacement of one
hydrogen in chloromethane by a methyl group to
form chloroethane reduces the rate of SN2
displacement of the chlorine atom by about a
factor of 100. Replacement of the hydrogen by an
ethyl group to form chloropropane reduces the
reate of SN2 displacement of the chlorine atom by
another factor of 2.
The gauche confomer in the 1-propyl case has
similar reactivty to the ethyl case.
43
Replacement of a hydrogen in a halomethane by a
carbon chain of 3 or more atoms shows no
additional effect over a carbon chain of 2 atoms.
44
Branching next to the reacting carbon also
retards substitution.
Multiple substitution at the position next to the
electrophilic carbon causes a dramatic decrease
in reactivity in SN2 substitution
reactions. 1-Bromo-2,2-dimethylpropane is
virtually inert.
45
The explanation for the decrease in reactivity is
in the stabilities of the transition states
involved
In 1-bromo-2-methylpropane two gauche
methyl-halide interactions occur in the only
conformation pemitting nucleophilic attach by the
OH-. In 1-bromo-2,2-dimethylpropane there is no
conformation allowing easy approach of the OH-
and the reaction is blocked almost completely.
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Important Concepts
6

• Haloalkane An alkyl halide, an alkyl group and
  a halogen
• Haloalkane Properties Strongly affected by the
  C-X bond polarization and the polarizability of
  X.
• Nucleophilic When a lone pair of electrons on
  a reagent attacks a positively polarized (or
  electrophilic) center. If a substituent is
  replaced, the reaction is termed a nucleophilic
  substitution. The substituent replaced is called
  the leaving group.
• Nucleophilic Substitution Kinetics For primary
  and most secondary haloalkanes the reaction is
  2nd order. These reactions are termed SN2. They
  are concerted reactions where bonds are
  simultaneously made and broken.

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Important Concepts
6

• SN2 Reactions are Stereospecific - These
  reactions proceed by backside displacement. The
  configuration at the reacting center is inverted.
• SN2 Transition State
• sp2 carbon center
• Partial bond making at nucleophile and
  electrophilic carbon.
• Partial bond breaking at leaving group and
  electrophilic carbon
• Both nucleophile and leaving group bear partial
  charges.
• Leaving Group Ability - Roughly proportional to
  the strength of the conjugate acid (especially
  good leaving groups chloride, bromide, iodide,
  sulfonates).
• Nucleophilicity Increases
• With negative charge
• Farther to the left and down in periodic table
• In aprotic solvents.

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Important Concepts
6

• Polar Aprotic Solvents - Accelerate SN2
  reactions.
• Branching At The Reactive Center - (or at the
  carbon next to it) sterically hinders the
  transition state and decreases the rate of SN2
  substitution.