Transcript lec-1- 211 ( N-Subs)..

Pharmaceutical Organic
Chemistry
211 PHC lect.1
Dr. Ebtehal S AlAbdullah
[email protected]
Topics to be covered:
Three parts:
Part one: Stereochemistry
Part two: Classes and Mechanism of reactions
a- Subsitiution
b- addition
c- elimination
d- rearrangement
e- Free radicals
Part three: Heterocyclic chemistry
LEC. 1
Pharmaceutical Organic Chemistry
Part two:
Classes and Mechanisims of Organic reactions
Dr. Ebtehal al abdullah
[email protected]
Classes of Organic compounds
and functional group
A functional group is an atom or a group of atoms with
characteristic chemical and physical properties. It is the
reactive part of the molecule.
 Reactions and Their Mechanisms
 There are four general types of organic reactions
 Substitutions
 Additions
O Reactions and Their Mechanisms
O Eliminations
O
Rearrangements
 Cleavage of Covalent Bonds
 Homolytic cleavage: each atom involved in the covalent bond receives one
electron, resulting in formation of free radical
 Hetrolytic cleavage: both bonding electrons are retained by one of the atoms,
resulting in formation of ionic species
10
 Heterolysis of Bonds to Carbons: Carbanions and
Carbocations
 Reaction can occur to give a carbocation or carbanion
depending on the nature of Z
11
 Heterolysis of Bonds to Carbons: Carbanions and
Carbocations
 Carbocations have only 6 valence electrons and a positive charge
 Carbanions have 8 valence electrons and a negative charge
12
 Organic chemistry terms for Lewis acids and bases
 Electrophiles (“electron-loving” reagents ): seek electrons to
obtain a stable valence shell of electrons
 Are electron-deficient themselves e.g. carbocations
 Nucleophiles (“nucleus-loving” reagents): seek a proton or some
other positively charged center
 Are electron-rich themselves e.g. carbanions
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
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)
Substitution reactions
The SN1 Mechanism
Nucleophilic Substitution Reaction of alkyl halide
SN1 reaction
unimolecular nucleophilic substitution, two-step mechanism
Step1: ionization and formation of R+
R
X
slow
R+
+
X-
Carbonium ion
Step2: combination of R+
R+
+ Nu:
fast
RNu:
Cont. SN1 reaction
 The rate of chemical reaction is a measure of how fast the reaction
proceed,
 It dose not depend on the conc. Of Nu-, depend on only conc. Of RX
 It follow first order kinetic, depend only on reactant conc.(RX)
It is nuimolecular reaction [ because only one particle (RX) is involved
in the transition state of rate determining step

R
X

R----------X
transition state
from one particle
R+
+
X-
Cont. SN1 reaction

R
X

R----------X
R+
+
X-
transition state
from one particle
The rate-determinig step in SN1 reaction involves the formation of R+,
So, increasing the stability of R+ will increase the rate of the reaction
C6H5CH2+, CH2=CHCH2+, (CH3)3C+, (CH3)2CH+, CH3CH2+, CH3+
Decreasing the stability of R+, decreasing SN1 rate of RX
* Only benzylic, allylic and 3°R+ undergo SN1
The SN1 Mechanism
1)
CH3
CH3 C
CH3
CH3
slow
CH3 C
+
: Br:
..
CH3
.. _
: Br :
..
+
carbocation
2)
CH3
CH3 C
+
CH3
CH3
+ : Nu
_
fast
CH3 C
Nu
CH3
Energy Diagram for a Typical SN1
Reaction:
t.s.1 ?
t.s. 2 ?
Carbocation
intermediate
E
(CH3)3CBr + H2O
+
(CH3)3COH2
Progress of reaction
R
R
R
R
+
R
Nu
R
R
Nu
R
Br
R
Nu
R
R C R
R
Br
C R
R
Nu
+R
R C
R
energy
intermediate
R
R
R C R
Br
R
C R
Nu
Reaction coordinate
Cont. SN1 reaction
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
When a strong Nu as CN- is used,
3° RX undergo SN1 reaction exclusively, where as
SN1
H2O or ROH
C6H5CH2X or
CH2=CHCH2X
SN2
CN-
C6H5CH2OH or CH2=CHCH2OH
C6H5CH2CN or CH2=CHCH2CN
Cont. SN1 reaction
Proplems
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
Substitution reactions
The SN2 Mechanism
NUCLEOPHILIC SUBSTITUTION REACTION OF ALKYL HALIDE
SN2 reaction
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
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]
Cont. SN2 reaction
 The rate of second order, 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-
Energy Diagram of SN2 Reaction
Energy of T. S.
Potential
Energy
(E)
Eact
∆H for reaction
Average energy
of reactants
Average energy
of products
Progress of reaction
OH
H
R
H
+
R
OH
H
+
H
Br
H
R
O
C
H
H
Br
energy
H
.. __
O:
..
R
H
C
H
Br
Reaction coordinate
OH
R C H
H
Br
Br
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
Summary of SN1 & SN2 Mechanisms
SN2
SN1
 A bimolecular reaction
 A unimolecular reaction
 Back-side attack
 An ionization reaction
 2ed 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
Factors Regulate SN2 and SN1 Mechanism
2) Nature of the nucleophile
3) Nature of the solvent
4) Nature of the halogen atom
Relative Nucleophilicity
CH3OH
H2 O
_
OH
O
CH3 C
_
O
_
O
_
OCH3
_
I
_
SH
_
N
C
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
Nuclephiles
Strong small Nu- (( SN2))
-OH,
CH3O- , CH3CH2O- , CN- , RS- , RC≡C- , Br- , I-
Weak small Nu- (( SN1))
H2O , CH3OH, EtOH, RSH, F- , CH3COO- ,
Nature of Solvent
SN2 : low to moderate polar solvent
as acetone, DMF
SN1 : moderate to high polar solvent
as water, MeOH, EtOH
SN2 Reaction: Leaving Groups
 Best leaving groups leave to form weak Lewis bases.
 Good leaving groups:
 Br, I, Cl,OH2+
 “Lousy” leaving groups:
 OH, OR, NH2,, F
WWU -- Chemistry
Study Proplem
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
Examples on SN2 Reaction
 CH3CH2Cl
+ HO-
 CH3CH2Br
+ HS-
CH3CH2SH + Br-
 CH3CH2I
+ RO-
CH3CH2OR + I-
+ RS..
 CH3CH2Cl + H2N
CH3CH2SR + Br-
 CH3CH2Br
CH3CH2OH + Cl-
CH3CH2NH2 + Cl-
 CH3CH2Br
+ RCC-
CH3CH2CCR + Br-
 CH3CH2I
+ NC-
CH3CH2CN + I-
Linkage with the life sciences
Information Enrichment
MEDICALL YSPEAKING
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.
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