Pharmaceutical Organic Chemistry 211 PHC lect.1 Dr. Ebtehal S AlAbdullah ebtehalksu@yahoo.com

Textbooks: R. Fessenden and J. Fessenden, Organic Chemistry, PWS Publishers, Latest edition. Optional reading : Joule and Smith, Heterocyclic Chemistry, Van Nostrand Reinhold, Latest edition.

Aim of the Course The Course is Designed to Provide the Students with: 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.

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

COURSE EVALUATION Credits Type 15 Midterm I 1 Midterm II 2 25 Practical Exam 3 5 Term Activity* 4 20 + 20 Final exam *Homework and Classroom Assignments and Discussion

LEC. 1 Dr. Ebtehal al abdullah Pharmaceutical Organic Chemistry ebtehalksu@yahoo.com Pharmaceutical Organic Chemistry Part One: Classes and Mechanisims of Organic reactions

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.

Reactions and Their Mechanisms There are four general types of organic reactions Substitutions Additions

Reactions and Their Mechanisms Eliminations 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

Heterolysis of Bonds to Carbons: Carbanions and Carbocations Reaction can occur to give a carbocation or carbanion depending on the nature of Z

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

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

Substitution Reaction In this type of reaction one atom, ion, or group is substituted for another. Its two types: Nucleophilic Substitution Reaction Electrophilic Substitution Reaction

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+ Step2: combination of R+

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

* Only benzylic, allylic and 3°R+ undergo SN1 Cont. SN1 reaction 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+ Decresing the stability of R+, decreasing SN1 rate of RX * Only benzylic, allylic and 3°R+ undergo SN1

The SN1 Mechanism carbocation

When weak Nu such as H2O or ROH is used the rate of SN1 reaction 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 C6H5CH2OH or CH2=CHCH2OH C6H5CH2X or CH2=CHCH2X C6H5CH2CN or CH2=CHCH2CN SN1 H2O or ROH SN2 CN-

Cont. SN1 reaction Proplems 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

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]

Increase the steric hindrance around the halogenated carbon Decreases 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-

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

Summary of SN1 & SN2 Mechanisms 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

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.

Chlorambucil