1-What is substitution reaction? 2-What are can ... · • In substitution reaction of alkyl...
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Transcript of 1-What is substitution reaction? 2-What are can ... · • In substitution reaction of alkyl...
1-What is substitution reaction?
2-What are can Nucleophilic Substitution
Reaction?
3- SN1 reaction.
4-SN2 reaction
5- mechanisms of SN1&SN2
1- SUBSTITUTION REACTIONS
Its two types:
A. Nucleophilic Substitution Reaction
B. Electrophilic Substitution Reaction
1-Substitution Reaction
In this type of reaction one atom, ion,
or group is substituted for another.
R X + Y R Y + X
X is called leaving group, a term meaning any group that can be
displaced from a carbon atom.
• Halide ions are good leaving groups as they are very week bases.
• Strong bases such as OH- are very poor leaving group.
• In substitution reaction of alkyl halides, the Iodide ion is the halide most
easily displaced.
RF RCl RBr RI
Increase of Reactivity
The species that attacks an R “usually alkyl” in substitution
reaction is called a nucleophile (abbreviated Nu:-).
Generally, a nucleophile is any species that is attracted to
positive center. It is a Lewis base.
Most nucleophiles are anions, however, some neutral polar
molecules such as H2O, CH3OH, CH3NH2 can also act as
nucleophiles by their unshared electrons that can be used to
form sigma bonds.
Substitutions by nucleophiles are called nucleophilic
substitution or nucleophilic displacement.
The electrophile (abbreviated E+) is any species that is attracted
toward a negative center. It is a Lewis acid.
Some common electrophiles and nucleophiles
common
electrophiles (E+)
Common
nucleophiles (Nu:-)
H+ (HCl)
R+ (R-X)
R-C+=O (RCOX)
NO2+ (HNO3)
X+ (X2)
AlCl3
AlBr3
OH- (H2O), RO
- (ROH), RCOO
-
Na+N
-H2, R3N:
X- (Cl
-, Br
-)
Na+CN
-
R-Mg
+X, Ar
-Mg
+X
(R)2C=C(R1)2
C6H6
A. Nucleophilic Substitution Reaction
Q: What is nucleophilic substitution reaction?
A reaction in which Nu is substituted by another Nu
can occur by an: a. SN1 path
b. SN2 path
Most common reaction of alkyl halides (RX) and alcohols (ROH)
A species which has ability to donates a pair of electrons is
termed as a nucleophile
Nucleophilic Substitution Reactions
The SN1 Mechanism
SN1 Reaction Unimolecular Nucleophilic Substitution
It is a 2 step mechanism involving:
1. Slow: (rate determining) step - ionization of the alkyl halide to
form a carbocation (Carbonium ion)
R X R + XSlow
2. Fast step : addition of the nucleophile to the carbocation
(Carbonium ion)
R + NuFast RNu
1)
2)
3)
: :..
slow
++ : Br :
..
..
_
++ : :
fast
:+
:+
fast
:..
+ H+
CH3
C CH3
CH3
Br
CH3
C CH3
CH3
CH3
C CH3
CH3
CH3
C CH3
CH3
O H
H
O
H
H
CH3
C CH3
CH3
O H
H
CH3
C CH3
CH3
O H
carbocation
The SN1 Mechanism Acetone is used to dissolve everything! Water
is the solvent and nucleophile (solvolysis).
(CH3)3CBr + H2O
Carbocation
intermediate
(CH3)3COH+H+
t.s.1 ?
t.s. 2 ?
Progress of reaction
E
R CR
R
Nu
R CRR
Br
This sequence of reactions can be represented on an energy diagram. The formation of the
carbocation (carbonium ion) is the high energy (slow) step. Addition of the nucleophile to the
carbocation (carbonium ion) is very rapid.
R
H
CH3 BrC
H
RCH3 O H
OH
H
CH3 R
OH
H
RCH3
+
+
enantiomers
SN1 Reaction: stereochemistry
planar
carbocation
sp2
(S) (R)
(R)
50%
50%
RACEMIZATION
-
attacks top
and bottom
equally
CH3
H
CH3C
Et
Br
Pr CH3-O-H
CH3C
Et
O
Pr
3o substrate
polarproticsolvent!
C
Pr
H3C Et
(S) enantiomerplanar carbocation
C
Pr
H3C Et
front sideattack
back sideattack
CH3-O-H
CH3-O-H
Slow
Pr
CH3Et
OH3C
H
Pr
CH3Et
OH3C
CHEt
O
Pr CH3H
H
50% (S)
50% (R)
Fast fast
fast
C6H5CH2X or C6H5CH2OH or CH2=CHCH2OH
CH2=CHCH2X C6H5CH2CN or CH2=CHCH2CN
SN1
H2O or ROH
SN2
CN-
The SN1 Mechanism
2) 3° RX undergo SN1 reaction exclusively
3) When weak Nu such as H2O or ROH is
used the rate of SN1 reaction Is in the
following order:
C6H5CH2X > CH2=CHCH2X > 3° RX
4) When a strong Nu as CN- is used 3°
RX undergo SN1 reaction exclusively,
C
tertiary
C
tertiary secondary
>
primary
+
carbocation (very stable)
secondarycarbocation
+
CH3
>Br
CH3
CH3
CH3
CH
CH3
Br
CH3
CH
CH3
CH3
CH3-CH
2-Br
CH3
+
primarycarboc
CH3
carbocation(unstable)
CH3
+
CH3-Br>
very unstable carbocation
three methyl groups
two methyl groups
one methyl group
no methyl groups
CH3
CH2
1) The rate of SN1 reaction Is in the
following order
SN1 Reaction: kinetics
The 1 indicates that the reaction is unimolecular - only
one reactant is involved in the slow step of the reaction.
The rate depends only on the concentration of the alkyl
halide, not the nucleophile.
SN1 does not involve the nucleophile in the rate determining step.
Thus nucleophile has no effect on the reaction rate.
• Usually SN1 reactions are run in polar protic solvents, compounds with O-H groups, as Polar solvent stabilizes the carbocation!
• The polar protic solvent acts as BOTH nucleophile as well as the
solvent.
• Common solvent/nucleophiles include:
water, ethanol, methanol, acetic acid, and formic acid.
SN1 Reaction solvents
SN1 reactions prefer polar-protic solvents that can solvate the anion and cation
formed in the rate-determining step.
R-X R+ + X-
rate-determining
step
solvation of both ions
speeds the ionization
Carbocation
ions
SN1 Reaction solvents
• Usually SN1 reactions are run in polar protic solvents, compounds with O-H groups, as Polar solvent stabilizes the carbocation!
• The polar protic solvent acts as BOTH nucleophile as
well as the solvent in SN1 reactions - solvolysis:.
• Common solvent/nucleophiles include:
water, ethanol, methanol, acetic acid, and formic acid.
WaterH
OH
Methanol HO
CH3
HO
CH2CH3
HOEtEthanol
HO
C
O
CH3Acetic acid HOAc
HO
C
O
HFormic acid
HOMe
NONPOLAR
POLAR
Polar Protic Solvents
Nonpolar Polar Aprotic Solvents
SN2
SN1
+
-
CH3COOH
CH3CH2OH
CH3OH
HCOOH
CF3CH2OH
H2O
CF3COOH
CH3CH2CH2CH2CH3
CCl4
CH3CH2 O CH2CH3
S CH3CH3
O
CCH3 CH3
O
H C N
O
CH3
CH3
SN1 Reaction solvents
WaterH
OH
Methanol HO
CH3
HO
CH2CH3
HOEtEthanol
HO
C
O
CH3Acetic acid HOAc
HO
C
O
HFormic acid
HOMe
Q1: List the following carbocation in order of increasing stability
Q2: Which of the following compounds is more reactive toward SN1
reaction. Explain why
1. C6H5CH2Br 2. CH3Br 3. CH2=CHCH2Br
CH2 C(CH3)21. 3.2.
H.W -1
Substitution Reactions
The SN2 Mechanism
Transition state
SN2 Reactions
Bimolecular nucleophilic substitution, one-step mechanism, which
involves a transition state.
Nu attacks from back-side
Bimolecular reaction, because both Nu and RX are involved in the transition state.
The SN2 mechanism:
a) is a single step process
b) involves no intermediates
c) involves only one transition state, which is of
low polarity
d) follows second order (bimolecular) kinetics.
That is,
rate=k[substrate][nucleophile]
SN2 Reactions
It is second order reaction , because it is proportional to conc. Of Nu & RX
Increase the steric hindrance around the halogenated carbon Decreases
the rate of SN2 reaction.
3° RX are too hindered to undergo SN2 reaction.
CH3X RCH2X R2CHX
increasing steric hindrance , decreasing SN2 rate
CH3X…… most reactive
2 ° [R2CHX ]…… react slowly
3 ° [R3X ] …….no react by SN2
When strong Nu as CN- is used, the SN2 rate in the following order
benzylic halide > Allylic halide > Methyl halide
** CH3X and RCH2X (1° RX) undergo SN2 exclusively, irrespective of
the strength of Nu-
SN2 Reactions
Progress of reaction
Potential Energy
(E)
Energy of T. S.
Average energy of reactants
Average energy of products
∆H for reaction
Eact
..:
..
__
H O
C
Br
R
Br
H O
C
C
H
H
Br-
OH
R
R
H
H
Br
+ R
OH
H
H
+ BrOH
SN2 Reactions Mechanism
one step
transition state
PHC 211/ Dr. Ahmed M. Alafeefy
C X
R3
RR1
Nu
C X
R3
RR1
Nu C X
R3
RR1
Nu +
O
C
R
H
CH3
H O : ..
..
attacks
back lobe
nucleophilic attack
(R)-config.
(S)-config.
C
R
H
CH3
Br : : ..
.. H : ..
..
INVERSION
SN2 Reactions Mechanism
C Cl:
CH3
H
..
..
SN2 ANIMATION
ENERGY PROFILE
R
Press the slide show button to see the animation. Press ESC to finish.
SN2 Reactions Mechanism
C Cl:
CH3
H
:Br: ..
..
..
..
SN2 ANIMATION
ENERGY PROFILE
R
SN2 Reactions Mechanism
C Cl:
CH3
H
:Br: ..
..
..
..
SN2 ANIMATION
ENERGY PROFILE
R
SN2 Reactions Mechanism
C Cl:
CH3
H
..
.. :Br: ..
..
SN2 ANIMATION
ENERGY PROFILE
R
SN2 Reactions Mechanism
C Cl:
R
CH3
H
..
.. :Br: ..
..
SN2 ANIMATION
ENERGY PROFILE SN2 Reactions Mechanism
C
R
CH3 H
:Br ..
.. Cl: ..
..
SN2 ANIMATION
ENERGY PROFILE
Activated
Complex
Transition State
d- d-
SN2 Reactions Mechanism
C :Br ..
..
CH3
H :Cl: ..
..
SN2 ANIMATION
ENERGY PROFILE
R
SN2 Reactions Mechanism
C :Br ..
..
CH3
H :Cl: ..
..
SN2 ANIMATION
ENERGY PROFILE
R
SN2 Reactions Mechanism
C :Br ..
..
CH3
H :Cl: ..
..
SN2 ANIMATION
ENERGY PROFILE
R
SN2 Reactions Mechanism
C :Br ..
..
CH3
H
SN2 ANIMATION
ENERGY PROFILE
R
SN2 Reactions Mechanism
○ Stereochemistry of SN2 Reactions
When the nucleophile attacks in an SN2 it is on the opposite side to the position
of the leaving group. As a result, the reaction will proceed with an inversion of
configuration.
C Br
H3C
C6H13
H
Br+HO
C Br
CH3
C6H13H
HO C
CH3
C6H13
H
HO
(R)-(-)-2-Bromooctane (S)-(+)-2-Octanol
SN2 Reactions Mechanism
The rate depends on both the concentration of the R-X and the nucleophile.
(R) (S)
o Effects of R-
Reactivity order
CH3- > CH3CH2- > (CH3)2CH- > (CH3)3C-
The rate of SN2 reaction is inversely proportional to the streic
hindrance around the carbon attached to the leaving group.
SN2 Reactions Mechanism
> > C
primary secondary tertiary
CH3-Br CH
3-CH
2-Br CH
3CH
CH3
Br > CH3
CH3
CH3
Br
Reactivity order---- fastest to slowest!
SN2 - SUBSTRATE
C
R
Br :
H O : ..
..
R
R
large groups
introduce steric
hindrance
C
H
Br :
H O : ..
.. H
H
easy access
no steric
hindrance
SN2 Reactions Mechanism
Since the nucleophile is involved in the rate determining step, the nature of the
nucleophile is very important in an SN2 reaction. More reactive nucleophiles will
favor an SN2 reaction.
Effects of Nucleophile
RO- > HO- >>RCO2- > ROH > H2O
SN2 Reactions Mechanism
Increasing Nucleophilicty
H2O
CH3OH_ _
OCH3
_
I_ _
SH
_
C N
OH
_
CH3
C O
O
O
Relative Nucleophilicity
1) In general, stronger bases are better nucleophiles
2) However, iodide doesn’t fit that pattern (weak base, but great nucleophile!)
3) Cyanide is an excellent nucleophile because of its linear structure
4) Sulfur is better than oxygen as a nucleophile
NONPOLAR
POLAR
Polar Protic Solvents
Nonpolar Polar Aprotic Solvents
SN2
SN1
+
-
CH3COOH
CH3CH2OH
CH3OH
HCOOH
CF3CH2OH
H2O
CF3COOH
CH3CH2CH2CH2CH3
CCl4
CH3CH2 O CH2CH3
S CH3CH3
O
CCH3 CH3
O
H C N
O
CH3
CH3
SN2 Reaction solvents
WaterH
OH
Methanol HO
CH3
HO
CH2CH3
HOEtEthanol
HO
C
O
CH3Acetic acid HOAc
HO
C
O
HFormic acid
HOMe
SN2 reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not
solvate the nucleophile.
C
R
Br :
: .. ..
R
R
X :
SMALL,
UNSOLVATED
SN2 Reaction solvents
SN2 reactions are accelerated in polar, aprotic solvents
SN2 reactions are retarded (slowed) in polar, protic solvents
Examples on SN2 Reaction
CH3CH2Cl + HO- CH3CH2OH + Cl-
CH3CH2Br + HS- CH3CH2SH + Br-
CH3CH2I + RO- CH3CH2OR + I-
CH3CH2Br + RS- CH3CH2SR + Br-
CH3CH2Cl + H2N CH3CH2NH2 + Cl-
CH3CH2Br + RCC- CH3CH2CCR + Br-
CH3CH2I + NC- CH3CH2CN + I-
..
Q: Outline all steps in the mechansim of each of the following reaction:
1. C6H5CH2Br + NaCN C6H5CH2CN + NaBr
2. C6H5CH2Br + H2O C6H5CH2OH + HBr
3. (CH3)3CCl + CH3O-Na+ (CH3)3COCH3 + NaCl
H.W -2
Which member of the following pairs of compounds will react
more rapidly with Nu in an SN2 reaction? Explain
a.
b.
c.
Br CH2CH2Br
CH3CH2CH2Cl or CH3CHCH3
CH3
or
orCl I
d.CH3CH2CH2CH2Cl or H3CC
CH3
CH3
Cl
H.W -3
General concepts for SN1 & SN2
Protic solvents:
“…those that contain -OH or -NH groups
…worst solvents for SN2 reactions.”
Aprotic solvents: “…have strong dipoles but don’t have
-OH or -NH groups. Best for SN2
reactions.”
Typical protic solvents:
water, methanol, ethanol, acetic acid, formic acid
Typical aprotic solvents:
acetone, DMF, DMSO, acetonitrile
Solvents
SN2
A bimolecular reaction
Back-side attack
2ed order in rate
Inversion of configuration
CH3X > 1oRX > 2oRX
SN1
A unimolecular reaction
An ionization reaction
1st order in rate
No inversion of configuration
3oRX > 2oRX
Summary of SN1 & SN2 Mechanisms
Benzylic and allylic undergo both type of substitution
SN1 & SN2 Mechanisms
Depending on the strength of Nu
if weak Nu ……… SN1
if strong Nu ………. SN2
Summary of SN1 & SN2 Mechanisms
Energy required for 3o alkylhalid is very high, not obtained even with heating,
but tertiary alkylhalid is very reactive and proceed via SN1 reaction.
Factors Regulate SN2 and SN1 Mechanism
1) Nature of the nucleophile
2) Nature of the solvent
3) Nature of the halogen atom
Linkage with the life sciences
Information Enrichment
Medically Speaking
Pharmacology And Drug Design
Pharmacology is the study of how drugs interact
with biological systems, including the mechanisms
that explain drug action.
Pharmacology is a very important field of study
because it serves as the basis for the design of new
drugs.
Chlorambucil
