Pharmaceutical Organic Chemistry 211 PHC lect.1 Dr. Ebtehal S AlAbdullah

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: 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.

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 CreditsType 15 Midterm I 1 15 Midterm II 2 25 Practical Exam 3 5 Term Activity* Final exam 5 *Homework and Classroom Assignments and Discussion

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

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

O Reactions and Their Mechanisms O Eliminations O Rearrangements

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

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

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

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

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. S N 1 path b. S N 2 path Most common reaction of alkyl halides (RX) and alcohols (ROH)

Substitution reactions The S N 1 Mechanism

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+

 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

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 3°R+ undergo S N 1 Cont. S N 1 reaction

The S N 1 Mechanism carbocation

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

energy Reaction coordinate + intermediate

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

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

Substitution reactions The S N 2 Mechanism

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

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. 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-

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

energy Reaction coordinate

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

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

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

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.

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

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

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

Study Proplem Which member of the following pairs of compounds will react more rapidly with Nu in an SN2 reaction? Explain

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 -..

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