Pharmaceutical Organic Chemistry 211 PHC –lec. 3 Dr. Ebtehal S AlAbdullah ebtehalksu@yahoo.com

LECTURE CONTENTS: Classes and Mechanisims of Organic Reactions 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 (-H2O) of alcohols and R-X Dehydrohalogenation (-HX) of alkyl halides

Elimination reaction 1. removal of a proton There are three fundamental events in these elimination reactions: 1. removal of a proton 2. formation of the CC p bond 3. breaking of the bond to the leaving group

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

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 VERSUS SUBSTITUTION IN R-X Both reactions involve heating the R-X under reflux with KOH or NaOH Elimination R-X also undergo elimination reactions in the presence of sodium or potassium hydroxide. 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 halogenoalkane substitution or elimination? primary mainly substitution secondary both substitution and elimination tertiary mainly 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 H2O is lost in the elimination, this reaction is called dehydration

The mechanism - a simplified version

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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 CH3CH2OH + NAD+ ---> CH3CH=O + NADH + H+ 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. CH3CH2OH + NAD+ ---> CH3CH=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:

Carbocation Rearrangement a carbocation

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 WWU -- Chemistry

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Types Kappa chain: V-J rearrangements Lambda chain: V-J rearrangements Gene rearrangement is a mechanism of genetic recombination in the early stages of immunoglobulin (Ig) and T cell receptors (TCR) production of the immune system. V(D)J recombination takes place in the primary lymphoid tissue (the bone marrow for B cells, and Thymus for T cells) Types Kappa chain: V-J rearrangements Lambda chain: V-J rearrangements Hodgkin's disease which is a cancer originating from white blood cells called lymphocytes. Hodgkin's lymphoma is characterized by the orderly spread of disease from one lymph node group to another and by the development of systemic symptoms with advanced disease.

Free radical reaction 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.

Mechanism of the Reaction Free radical addition is an addition reaction  The addition may occur between a radical and a non-radical, or between two radicals. Radical chain mechanism are: Initiation by a radical initiator: A radical is created from a non-radical precursor. Chain propagation Chain termination: Two radicals react with each other to create a non-radical species

Chlorination of Methane hv CH4 + Cl2 CH3Cl + CH2Cl2 + CHCl3 + CCl4 + HCl It is a very complicated free radical reaction.

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

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. 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.

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.