Pharmaceutical Organic
Chemistry
By
Dr. Mehnaz Kamal
Assistant Professor
Pharmaceutical Chemistry
Prince Sattam Bin Abdulaziz University
WELCOME
1-What is Substitution reaction?
2-What are Nucleophilic Substitution Reaction?
3-SN1 reaction.
4-SN2 reaction.
5- Mechanisms of SN1 & SN2.
1- SUBSTITUTION
REACTIONS
1-Substitution Reaction
In this type of reaction one atom, ion,
or group is substituted for another.
Its two types:
A. Nucleophilic Substitution Reaction
B.
Electrophilic Substitution Reaction
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 weak 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
substitution or nucleophilic displacement.
called
nucleophilic
 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),
RCOONa+N-H2,
R3N:
X- (Cl-, Br-)
Na+CNR-Mg+X, Ar -Mg+X
(R)2C=C(R1)2
C6H6
A. Nucleophilic Substitution Reaction
Q: What is nucleophilic substitution reaction?
A species which has ability to donates a pair of electrons is
termed as a nucleophile
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)
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)
Slow
R
X
R +
X
2. Fast step: addition of the nucleophile to the carbocation
(Carbonium ion)
Fast
R
+
Nu
RNu
The SN1 Mechanism
 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.
1)
CH3
CH3 C
CH3
CH3
slow
CH3 C
+
: Br:
..
CH3
.. _
: Br :
..
+
R
R C R
t.s.1 ?
t.s. 2 ?
Br
R
2)
CH3
CH3 C
+
H
CH3
+ :O:
CH3
fast
CH3 C
H
:O
carbocation
3)
:O
H
+
H
H
E
Carbocation
intermediate
(CH3)3CBr + H2O
CH3
CH3
+
CH3
H
CH3
CH3 C
C R
R
Nu
fast
CH3 C
:O
..
CH3
H
+
H
+
(CH3)3COH+H+
Progress of reaction
SN1 Reaction: stereochemistry
R
CH3
H
Br
(R)
50%
sp2
CH3
planar
carbocation
+
C
R
H
O H
attacks top
and bottom
equally
50%
OH
OH
CH3
(S)
+
H
R
R
enantiomers
H
RACEMIZATION
CH3
(R)
Slow
Pr
C
CH3-O-H
Pr
C Br
polar
H3C
protic
Et
3o substrate solvent!
(S) enantiomer
H3C Et
planar carbocation
CH3-O-H
front side
attack
Pr
C
H3C Et
CH3-O-H
Fast
back side
attack
Pr
H3C
Et
H3C
H
C O
CH3
H
Pr
H
fast
Pr
H
O
CH3
Et
fast
H
Et
H3C
C O
CH3
50% (S)
Pr
O
CH3
Et
50% (R)
The SN1 Mechanism
CH3
1) The rate of SN1 reaction Is in the
following order
CH3
Br
C
>
CH3
tertiary
3) When weak Nu such as H2O or ROH is
used the rate of SN1 reaction Is in the
following order:
secondary
CH3
CH3
C+
Br > CH3-CH2-Br
> CH3-Br
CH3
CH3
2) 3° RX undergo SN1 reaction exclusively
CH
primary
+
CH3
CH
+
CH3
+
CH 2
CH3
CH3
CH3
C6H5CH2X > CH2=CHCH2X >
3° RX
4) When a strong Nu as CN- is used 3°
RX undergo SN1 reaction exclusively,
C6H5CH2X or
CH2=CHCH2X
tertiary
carbocation
(very stable)
three methyl
groups
SN1
H2O or ROH
SN2
CN-
secondary
carbocation
two methyl
groups
primary
carboc
carbocation
(unstable)
very unstable
carbocation
one methyl
group
no methyl
groups
C 6H5CH2OH or CH2=CHCH2OH
C6H5CH2CN or CH2=CHCH2CN
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.
SN1 Reaction solvents
•
•
Usually SN1 reactions are run in polar protic solvents,
compounds with O-H groups, as Polar solvent stabilizes
the carbocation!
Water
Methanol
H
The polar protic solvent acts as BOTH nucleophile as
well as the solvent in SN1 reactions - solvolysis:.
Ethanol
H
Acetic acid
•
H
O
H
H
O
CH3
HOMe
O
CH2 CH3
HOEt
O
C CH3
O
Common solvent/nucleophiles include:
water, ethanol, methanol, acetic acid, and formic
acid.
Formic acid
H
O
HOAc
C H
O
SN1 reactions prefer polar-protic solvents that can solvate the anion and cation
formed in the rate-determining step.
ions
R-X
rate-determining
step
R+ +
X-
solvation of both ions
speeds the ionization
Carbocation
SN1 Reaction solvents
Polar Protic Solvents
POLAR
Nonpolar or Polar Aprotic
Solvents
CF3COOH
H2O
CH3
O+
S
CH3
H
C
CF3CH2OH
HCOOH
CH3OH
O
SN2
SN1
N CH3
CH3
O
CH3
CH3CH2 O
C
CH3CH2OHWater
CH3
H
CH3COOH
O
Methanol
H
Ethanol
H
H
O
CH3
HOMe
O
CH2 CH3
HOEt
O
C CH3
O
CH2CH3
CCl4
Acetic acid
H
CH3CH2CH2CH2CH3
Formic acid
H
O
C H
NONPOLAR
O
HOAc
H.W -1
Q1: List the following carbocation in order of increasing stability
1.
2.
CH2
3.
C(CH3)2
Q2: Which of the following compounds is more reactive toward SN1
reaction. Explain why
1. C6H5CH2Br
2. CH3Br
3. CH2=CHCH2Br
The SN2 Mechanism
Substitution Reactions
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.
Transition state
SN2 Reactions
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 Mechanism
..
:
H O
..
R
C
SN2 - SUBSTRATE
: Br
large groups
introduce steric
hindrance
R
R
..
:
H O
..
H
C
H
H
: Br
easy access
no steric
hindrance
SN2 Reactions Mechanism
OH
H
R
H
R
OH
+
H
+
Br
H
Br
Energy of T. S.
H
R
O
C
H
H
Br
Potential
Energy
(E)
Eact
transition state
∆H for reaction
one step
H
.. __
O:
..
R
Average energy
of reactants
H
C
Average energy
of products
H
Br
Progress of reaction
OH
R C H
H
Br
SN2 Reactions Mechanism
nucleophilic attack
..
:
H O
..
attacks
back lobe
R
(R)-config.
C
..
: Br :
..
CH3
H
INVERSION
R
..
:
H O
..
(S)-config.
C
CH3
H
SN2 Reactions Mechanism
ENERGY PROFILE
SN2 ANIMATION
R
H
CH3
Press the slide show button
C
..
Cl:
..
to see the animation. Press ESC to finish.
SN2 Reactions Mechanism
SN2 ANIMATION
R
..
:Br:
..
H
CH3
C
..
Cl:
..
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION
R
..
:Br:
..
H
CH3
C
..
Cl:
..
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION
R
..
:Br:
..
H
CH3
C
..
Cl:
..
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION
R
..
:Br:
..
H
CH3
C
..
Cl:
..
ENERGY PROFILE
SN2 Reactions Mechanism
ENERGY PROFILE
SN2 ANIMATION
R
..
:Br
..
d-
C
Transition State
.. dCl:
..
HCH
3
Activated
Complex
SN2 Reactions Mechanism
ENERGY PROFILE
SN2 ANIMATION
R
..
:Br
..
C
H
CH3
..
:Cl:
..
SN2 Reactions Mechanism
ENERGY PROFILE
SN2 ANIMATION
R
..
:Br
..
C
H
CH3
..
:Cl:
..
SN2 Reactions Mechanism
ENERGY PROFILE
SN2 ANIMATION
R
..
:Br
..
C
H
CH3
..
:Cl:
..
SN2 Reactions Mechanism
SN2 ANIMATION
R
..
:Br
..
C
H
CH3
ENERGY PROFILE
SN2 Reactions Mechanism
 The rate depends on both the concentration of the R-X and the nucleophile.
○ 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.
CH3
H3C
HO
C
Br
H
C6H13
(R)-(-)-2-Bromooctane
(R)
HO
C
CH3
Br
H C6H13
HO
C
+
Br
H
C6H13
(S)-(+)-2-Octanol
(S)
SN2 Reactions Mechanism
o Effects of R The rate of SN2 reaction is inversely proportional to the streic
hindrance around the carbon attached to the leaving group.
 Reactivity order
CH3- > CH3CH2- > (CH3)2CH- > (CH3)3CCH3
CH3-Br > CH3-CH2-Br >
CH3
CH
Br >
CH3
CH3
primary
secondary
Reactivity order---- fastest to slowest!
C
CH3
tertiary
Br
SN2 Reactions Mechanism
Effects of Nucleophile
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.
-
-
RO > HO
>>RCO2 >
ROH > H2O
Relative Nucleophilicity
CH 3 OH
H2O
_
OH
O
CH 3 C
_
O
_
O
_
OCH 3
_
_
I
SH
_
C
N
Increasing Nucleophilicty
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
SN2 Reaction solvents
Polar Protic Solvents
POLAR
Nonpolar or Polar Aprotic
Solvents
CF3COOH
H2O
CH3
O+
S
CH3
H
C
CF3CH2OH
HCOOH
CH3OH
O
SN2
SN1
N CH3
CH3
O
CH3
CH3CH2 O
C
CH3CH2OH
CH3
Water
CH3COOH
H
O
Methanol
H
Ethanol
H
H
O
CH3
HOMe
O
CH2 CH3
HOEt
O
C CH3
O
CH2CH3
CCl4
Acetic acid
H
CH3CH2CH2CH2CH3
Formic acid
H
O
C H
O
NONPOLAR
HOAc
SN2 Reaction solvents
SN2 reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not
solvate the nucleophile.
SN2 reactions are accelerated in polar aprotic solvents
SN2 reactions are retarded (slowed) in polar protic solvents
..
:..
X:
R
C
SMALL,
UNSOLVATED
R
R
: Br
Examples on SN2 Reaction
 CH3CH2Cl + HO-
CH3CH2OH + Cl-
 CH3CH2Br + HS-
CH3CH2SH + Br-
 CH3CH2I
CH3CH2OR + I-
+ RO-
 CH3CH2Br + RS-
CH3CH2SR + Br-
 CH3CH2Cl + H2N ..
CH3CH2NH2 + Cl-
 CH3CH2Br + RCC-
CH3CH2CCR + Br-
 CH3CH2I
CH3CH2CN + I-
+ NC-
H.W -2
Q: Outline all steps in the mechansim of each of the following reaction:
1. C6H5CH2Br + NaCN
2.
C6H5CH2Br + H2O
3. (CH3)3CCl
+ CH3O-Na+
C6H5CH2CN + NaBr
C6H5CH2OH + HBr
(CH3)3COCH3 + NaCl
H.W -3
Which member of the following pairs of compounds will react
more rapidly with Nu in an SN2 reaction? Explain
a.
Br
b.
CH3CH2CH2Cl
or
or
CH2CH2Br
CH3CHCH3
CH3
c.
Cl
or
I
CH3
d.
CH3CH2CH2CH2Cl
or
H3CC
CH3
Cl
General concepts for SN1 & SN2
Solvents
Protic solvents:
“…those that contain -OH or -NH groups
…worst solvents for SN2 reactions.”
Typical protic solvents:
water, methanol, ethanol, acetic acid, formic acid
Aprotic solvents:
“…have strong dipoles but don’t have
-OH or -NH groups. Best for SN2
reactions.”
Typical aprotic solvents:
acetone, DMF, DMSO, acetonitrile
Summary of SN1 & SN2 Mechanisms
S N2
S N1
 A bimolecular reaction
 A unimolecular reaction
 Back-side attack
 An ionization reaction
 2nd order in rate
 1st order in rate
 Inversion of configuration
 No inversion of configuration
 CH3X > 1oRX > 2oRX
 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
Energy required for 3o alkyl halide is very high, not obtained even with
heating, but tertiary alkyl halide 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 alkyl halide
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