Pharmaceutical Organic Chemistry 211 PHC lect.1 Dr. Ebtehal S
AlAbdullah [email protected]
Slide 2
Textbooks: R. Fessenden and J. Fessenden, Organic Chemistry,
PWS Publishers, Latest edition. Optional reading : Joule and Smith,
Heterocyclic Chemistry, Van Nostrand Reinhold, Latest edition.
Slide 3
Aim of the Course The Course is Designed to Provide the
Students with: R Recognize the various classes and subclasses of
organic compounds and how the chemical and physical properties
influence their behavior. Understand the chemical reactions unique
to each class or subclass of organic molecules and their role in
synthetic chemistry. Recognize the different reaction mechanisms
and their importance in synthesis. Understand the stereochemistry
of organic molecules and the stereochemical courses of organic
reactions. Understand the role of physicochemical properties,
mechanisms, and stereochemistry of organic molecules in biology and
pharmacy.
Slide 4
Topics to be covered: Three parts: Part one: Classes and
Mechanism of reactions a- Subsitiution b- addition c- elimination
d- rearrangement e- Free radicals Part two: Stereochemistry Part
three: Heterocyclic chemistry
Slide 5
COURSE EVALUATION CreditsType 15 Midterm I 1 15 Midterm II 2 25
Practical Exam 3 5 Term Activity* 4 20 + 20 Final exam 5 *Homework
and Classroom Assignments and Discussion
Slide 6
LEC. 1 Dr. Ebtehal al abdullah Dr. Ebtehal al
[email protected] Pharmaceutical Organic Chemistry Part
One: Part One: Classes and Mechanisims of Organic reactions Classes
and Mechanisims of Organic reactions
Slide 7
Classes of Organic compuonds 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.
Slide 8
Slide 9
Slide 10
Slide 11
O Reactions and Their Mechanisms O There are four general types
of organic reactions O Substitutions O Additions
Slide 12
O Reactions and Their Mechanisms O Eliminations O
Rearrangements
Slide 13
13 O Cleavage of Covalent Bonds O Homolytic cleavage: each atom
involved in the covalent bond receives one electron, resulting in
formation of free radical O Hetrolytic cleavage: both bonding
electrons are retained by one of the atoms, resulting in formation
of ionic species
Slide 14
14 O Heterolysis of Bonds to Carbons: Carbanions and
Carbocations O Reaction can occur to give a carbocation or
carbanion depending on the nature of Z
Slide 15
15 O Heterolysis of Bonds to Carbons: Carbanions and
Carbocations O Carbocations have only 6 valence electrons and a
positive charge O Carbanions have 8 valence electrons and a
negative charge
Slide 16
O Organic chemistry terms for Lewis acids and bases O
Electrophiles (electron-loving reagents ): seek electrons to obtain
a stable valence shell of electrons O Are electron-deficient
themselves e.g. carbocations O Nucleophiles (nucleus-loving
reagents): seek a proton or some other positively charged center O
Are electron-rich themselves e.g. carbanions
Slide 17
1- Substitution reactions
Slide 18
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
Slide 19
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. S N 1 path b. S
N 2 path Most common reaction of alkyl halides (RX) and alcohols
(ROH)
Slide 20
Substitution reactions The S N 1 Mechanism
Slide 21
Nucleophilic Substitution Reaction of alkyl halide S N 1
reaction unimolecular nucleophilic substitution, two-step mechanism
Step1: ionization and formation of R+ Step2: combination of R+
Slide 22
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 Cont. S N 1 reaction
Slide 23
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 C 6 H 5 CH 2 +, CH 2 =CHCH 2 +, (CH 3 ) 3 C +, (CH 3 )
2 CH +, CH 3 CH 2 +, CH 3 + Decresing the stability of R+,
decreasing S N 1 rate of RX * Only benzylic, allylic and 3R+
undergo S N 1 Cont. S N 1 reaction
Slide 24
The S N 1 Mechanism carbocation
Slide 25
Energy Diagram for a Typical S N 1 Reaction: (CH 3 ) 3 CBr + H
2 O Carbocation intermediate + (CH 3 ) 3 COH 2 t.s. 1 ? t.s. 2 ?
Progress of reaction E
Slide 26
energy Reaction coordinate + intermediate
Slide 27
When weak Nu such as H2O or ROH is used the rate of SN1
reaction Is in the following order C 6 H 5 CH 2 X > CH 2 =CHCH 2
X > 3 RX When a strong Nu as CN- is used, 3 RX undergo SN1
reaction exclusively, where as C 6 H 5 CH 2 OH or CH 2 =CHCH 2 OH C
6 H 5 CH 2 X or CH 2 =CHCH 2 X C 6 H 5 CH 2 CN or CH 2 =CHCH 2 CN S
N 1 S N 1 H 2 O or ROH S N 2 CN - CN - Cont. S N 1 reaction
Slide 28
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. C 6 H 5 CH 2 Br 2. CH3Br 3. CH
2 =CHCH 2 Br Cont. S N 1 reaction Proplems Proplems
Slide 29
Substitution reactions The S N 2 Mechanism
Slide 30
N UCLEOPHILIC S UBSTITUTION R EACTION OF ALKYL HALIDE S N 2
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
Slide 31
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]
Slide 32
Cont. S N 2 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 S N 2 reaction.
3 RX are too hindered to undergo S N 2 reaction. CH3X RCH2X R2CHX
increasing steric hindrance, decreasing S N 2 rate CH3X most
reactive 2 [R2CHX ] react slowly 3 [R3X ] .no react by S N 2 When
strong Nu as CN- is used, the S N 2 rate in the following order
benzylic halide > Allylic halide > Methyl halide ** CH3X and
RCH2X (1 RX) undergo S N 2 exclusively, irrespective of the
strength of Nu-
Slide 33
Energy Diagram of S N 2 Reaction Progress of reaction Potential
Energy (E) Energy of T. S. Average energy of reactants Average
energy of products H for reaction E act
Slide 34
energy Reaction coordinate
Slide 35
Q: Outline all steps in the mechansim of each of the following
reaction: 1. C 6 H 5 CH 2 Br + NaCN C 6 H 5 CH 2 CN + NaBr 2. C 6 H
5 CH 2 Br + H 2 O C 6 H 5 CH 2 OH + HBr 3. (CH 3 ) 3 CCl + CH 3 O -
Na + (CH 3 ) 3 COCH 3 + NaCl
Slide 36
Summary of S N 1 & S N 2 Mechanisms S N 2 A bimolecular
reaction Back-side attack 2 ed order in rate Inversion of
configuration CH 3 X > 1 o RX > 2 o RX S N 1 A unimolecular
reaction An ionization reaction 1 st order in rate No inversion of
configuration 3 o RX > 2 o RX
Slide 37
Summary of S N 1 & S N 2 Mechanisms Benzylic and allylic
undergo both type of substitution S N 1 & S N 2 Mechanisms
Depending on the strength of Nu if weak Nu S N 1 if strong Nu . S N
2
Slide 38
very high Energy required for 3 o alkylhalid is very high, not
obtained even with heating, but tertiary alkylhalid is very
reactive and proceed via S N 1 reaction.
Slide 39
2) Nature of the nucleophile 3) Nature of the solvent 4) Nature
of the halogen atom Factors Regulate S N 2 and S N 1 Mechanism
Slide 40
Relative Nucleophilicity 1) In general, stronger bases are
better nucleophiles 2) However, iodide doesnt 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
Slide 41
WWU -- Chemistry S N 2 Reaction: Leaving Groups O Best leaving
groups leave to form weak Lewis bases. O Good leaving groups: O Br,
I, Cl, OTs, OH 2 + O Lousy leaving groups: O OH, OR, NH 2,, F
Slide 42
Study Proplem Which member of the following pairs of compounds
will react more rapidly with Nu in an SN2 reaction? Explain
Slide 43
Examples on S N 2 Reaction CH 3 CH 2 Cl + HO - CH 3 CH 2 OH +
Cl - CH 3 CH 2 Br + HS - CH 3 CH 2 SH + Br - CH 3 CH 2 I + RO - CH
3 CH 2 OR + I - CH 3 CH 2 Br + RS - CH 3 CH 2 SR + Br - CH 3 CH 2
Cl + H 2 N CH 3 CH 2 NH 2 + Cl - CH 3 CH 2 Br + RCC - CH 3 CH 2 CCR
+ Br - CH 3 CH 2 I + NC - CH 3 CH 2 CN + I -..
Slide 44
Linkage with the life sciences Information Enrichment
Slide 45
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.