Pharmaceutical Organic Chemistry

Pharmaceutical Organic

Chemistry211 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 115 Midterm II 225 Practical Exam 35 Term Activity* 420 + 20 Final exam 5

*Homework and Classroom Assignments and Discussion

LEC. 1

Dr. Ebtehal al abdullahebtehalksu@yahoo.com

Pharmaceutical Organic Chemistry Part One: Classes and Mechanisims of Organic reactions

Classes of Organic compuondsand functional group

A functional group is an atom or a group of atoms withcharacteristic chemical and physical properties. It is thereactive part of the molecule.

OReactions and Their MechanismsO There are four general types of organic reactions

OSubstitutions

OAdditions

O Reactions and Their Mechanisms

OEliminations

O Rearrangements

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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

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O Heterolysis of Bonds to Carbons: Carbanions and CarbocationsO Reaction can occur to give a carbocation or

carbanion depending on the nature of Z

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O Heterolysis of Bonds to Carbons: Carbanions and CarbocationsO 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. 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+

R X R+ + X-

Carbonium ion

slow

R+ + Nu: RNu:fast

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-R----------X

transition statefrom one particle

Cont. SN1 reaction

R X R+ + X-R----------X

transition statefrom 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

+

Decresing the stability of R+, decreasing SN1 rate of RX

* Only benzylic, allylic and 3°R+ undergo SN1

Cont. SN1 reaction

The SN1 Mechanism1)

2)

: :..

slow+

+ : Br :..

..

_

++ : fast

CH3 C CH3

CH3

Br

CH3 C CH3

CH3

CH3 C CH3

CH3

CH3 C CH3

CH3

Nu

Nu _

carbocation

When weak Nu such as H2O or ROH is used the rate of SN1 reactionIs 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

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

CH2 C(CH3)21. 3.2.

Cont. SN1 reaction

Proplems

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 processb) involves no intermediatesc) involves only one transition state, which is of low polarityd) 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-

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

SN2 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

R-CH2-X + Nu_

R-CH2-Nu + X_

substrate nucleophile product leaving group

Oxygen Nucleophiles (SN2)

O-H_

R-CH2-O-Halcoholhydroxide

R-CH2-X + _+ X

O-R_

R-CH2-O-RR-CH2-X + _+ X

etheralkoxide

O-C-R_

R-CH2-R-CH2-X + _+ X

estercarboxylateO

O-C-R

O

Linkage with the life sciences

Information

Enrichment

MEDICALL YSPEAKINGPharmacology 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