Pharmaceutical Organic Chemistry 211 PHC –lec. 3 Dr. Ebtehal S AlAbdullah

LECTURE CONTENTS:  Classes and Mechanisims of Organic Reactions o Types of organic reaction ** Elimination ** Addition ** Rearrangement ** Free radical

Elimination reaction A reaction in which a molecule loses atom or group of atoms from its structure. Important method for preparation of alkenes commonly for R-OH Dehydration (-H 2 O) of alcohols and R-X Dehydrohalogenation (-HX) of alkyl halides

There are three fundamental events in these elimination reactions: 1. removal of a proton 2. formation of the C-C π bond 3. breaking of the bond to the leaving group E LIMINATION REACTION

Elimination reactions involving R-X 2-bromopropane 2-bromopropane The mechanism KOH and NaOH as strong bases

ELIMINATION VS SUBSTITUTION R-X Both reactions involve heating the R-X under reflux with KOH or NaOH Nucleophilic substitution The OH - present are good nucleophiles, and one possibility is a replacement of the X by an -OH group to give an alcohol via a nucleophilic substitution reaction. 2-bromopropane is converted into propan-2-ol.

Elimination R-X also undergo elimination reactions in the presence of sodium or potassium hydroxide. ELIMINATION VERSUS SUBSTITUTION IN R-X Both reactions involve heating the R-X under reflux with KOH or NaOH 2-bromopropane has reacted to give an alkene - propene

What decides whether you get substitution or elimination? The reagents you are using are the same for both substitution or elimination - the R-X and either NaOH or KOH. In all cases, you will get a mixture of both reactions happening - some substitution and some elimination.

What you get most of depends on a number of factors. 1. The type of halogenoalkane This is the most important factor. type of halogenoalkanesubstitution or elimination? primarymainly substitution secondaryboth substitution and elimination tertiarymainly elimination 2. The solvent Water encourages substitution. Ethanol encourages elimination. 3. The temperature Higher temperatures encourage elimination. 4. Concentration of the NaOH or KOH Higher concentrations favour elimination.

Elimination reactions involving ROH Alcohols, like RX undergo elimination reactions to yield alkenes because H 2 O is lost in the elimination, this reaction is called dehydration

The mechanism - a simplified version

Information Enrichment

Drug Metabolism Drug metabolism can occur in every tissue (e.g. gut, lung and kidney). However, the major drug metabolizing enzymes (DMEs) are expressed at the highest levels in the liver, which thus serves as the major organ of metabolic clearance Drug metabolism serves to control the exposure of a potentially harmful substance. Usually via oxidation of a lipophilic xenobiotic, DMEs increase the polarity and aqueous solubility thus facilitating its elimination from the body

Asian flush syndrome  Alcohol flush reaction (also known as Asian flush syndrome, Asian flush, Asian glow, among others) is a condition in which an individual's face or body experiences flushes or blotches as a result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol. It is commonly thought that the flush reaction is caused by an inability to metabolize alcohol.acetaldehyde CH 3 CH 2 OH + NAD + ---> CH 3 CH=O + NADH + H +

Rearrangement Reactions  In this type of reactions, some atoms/groups shift from one position to another within the substrate molecule itself, give a product with a new structure.

Rearrangement reactions  intramolecular atomic rearrangement, which involves migration or shift of atoms  involves a nucleophilic attack at electron deficient atoms e.g. C, O, N Often a substituent moves from one atom to another atom in the same molecule. In the example below the substituent R moves from carbon atom 1 to carbon atom 2:substituent

Carbocation Rearrangement a carbocation

WWU -- Chemistry A Closer Look... transition state

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

 Free radical, radical, have no charge.  It result from homolytic cleavage.  It is unstable, highly reactive molecule.  Pairs of electrically neutral "free" radicals are formed via homolytic bond breakage. Free radical reaction

Free radical addition is an addition reaction addition reaction The addition may occur between a radical and a non- radical, or between two radicals. Radical chain mechanism are: a) Initiation by a radical initiator: A radical is created from a non-radical precursor. Initiationradical initiator b)Chain propagationChain propagation c)Chain termination: Two radicals react with each other to create a non-radical speciesChain termination M ECHANISM OF THE R EACTION

Chlorination of Methane  CH 4 + Cl 2 CH 3 Cl + CH 2 Cl 2 + CHCl 3 + CCl 4 + HCl  It is a very complicated free radical reaction. hv

Linkage with the life sciences Information Enrichment

Oxidation  Oxidation is the beginning of the deterioration process. Think of how a slice of apple turns brown when exposed to air. Oxidation leads to the formation of free radicals which are unstable molecules in the body that have one unpaired electron. They can cause oxidation and damage to the cells. This is how some diseases start. Even eating a diet high in saturated fats, over cooked meats and processed foods over a long period of time can cause free radical damage.  Free radical damage can occur because of too much exposure to radiation, to smoke or because our cells have become overwhelmed by toxins in the environment. Even eating a diet high in saturated fats, over cooked meats and processed foods over a long period of time can cause free radical damage.

Home Work Find 3 different disease caused by free radical reactions inside the body

How Do Antioxidants Work?  Most people realize that we need antioxidants to prevent and fight disease but the role they play in maintaining your goal weight and even losing fat is not so widely known.  All antioxidants neutralize free radicals by either supplying the extra electron or breaking down them down.  Antioxidants help us stay vital into old age, detoxify our organs and protect our cells from free radical damage.  They support efficient metabolism helping us to lose fat more easily and they support healthy brain chemistry.