Pharmaceutical Organic Chemistry By Dr. Mehnaz Kamal Assistant Professor Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University

WELCOME WELCOME

1-To know classes and mechanisms of organic reactions 2- To know elimination reaction 3- To be differentiate between elimination & substitution 4-To understand rearrangement reaction 5- To understand free radical 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 Elimination reaction An elimination reaction is one where starting material loses the elements of a small molecule such as HCl or H 2 O or Cl 2 during the course of the reaction to form the product. There are three fundamental events in these elimination reactions: 1. removal of a proton 2. formation of the CC bond 3. breaking of the bond to the leaving group

Elimination, Unimolecular - E1 Elimination, Bimolecular - E2 Elimination reaction Types of Elimination reactions An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism. and the two-step mechanism is known as the E1 reaction and The one-step mechanism is known as the E2 reaction. The numbers do not have to do with the number of steps in the mechanism, but rather the kinetics of the reaction, bimolecular and unimolecular respectively

Elimination, Unimolecular - E1 Elimination reaction

 This mechanism is a two step process with the rate determining step being an ionization of the halide to produce a carbocation.The carbocation will then react with a base that can pull a β hydrogen off to produce the most stable alkene according to the Zeitsev Rule.Zeitsev Rule  The mechanism is similar to the S N 1 reaction except the second step involves a proton abstraction and π bond formation instead of a substitution.S N 1 reaction Elimination reaction Elimination, Unimolecular - E1 I) Dehydrohalogenation (-HX) of alkyl halides

The E1 Elimination Reaction (two steps) + :X:X slow fast carbocation 3 o > 2 o > 1 o Works best in a polar solvent. step one step two Weak base Elimination reaction Elimination, Unimolecular - E1 The removal of a β -hydrogen becomes difficult without a strong base and a different mechanism (ionization) begins to take place Alkyl Halides + Dil. Base or Conc. Acid + low heat I) Dehydrohalogenation (-HX) of alkyl halides β 

Zaitsev’s Rule + 2-butene 1-butene 19% 81% minor product major product Elimination reactions generally give the more highly substituted alkene. Elimination almost always gives a mixture of products. Elimination reaction Elimination, Unimolecular - E1 I) Dehydrohalogenation (-HX) of alkyl halides Dil. base

Elimination reaction Elimination, Unimolecular - E1 I) Dehydrohalogenation (-HX) of alkyl halides

II) Dehydration of alcohols Elimination of H 2 O from an alcohol using acid. H 2 SO 4 or H 3 PO 4 + H 2 O The dehydration reaction is acid-catalyzed. acid catalyst alcoholalkene R-OH R-R Elimination reaction Elimination, Unimolecular - E1 ∆

Mechanism of Dehydration acid catalyst protonated alcohol alcohol alkene carbocation acid catalyst Elimination, Unimolecular - E1 Elimination reaction

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 Elimination reaction

E1 occurs only 1) At zero or low base concentration 2) with solvolysis (the solvent is the base) 3) with tertiary and resonance capable substrates (alkyl halides) If a strong base is present in moderate to high concentration, or the substrate is a primary halide, the E2 reaction dominates. When The E1 Mechanism Occurs? Elimination reaction Elimination, Unimolecular - E1

Elimination, Bimolecular – E2 Elimination reaction

This mechanism is a One Step Elimination reaction Elimination, Bimolecular – E2 Alkyl Halide + Strong Base + High Heat For a Dehydrohalogenation Reaction

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

The Reaction is a  -elimination The functional group is attached to the  -carbo n.  -carbon  -carbon The  -hydrogen is attached to the  -carbon. Since the  -hydrogen is lost this reaction is called a  -elimination. Reagent = a strong base Elimination reaction Elimination, Bimolecular – E2

CC Cl H B: The Base Takes The  -hydrogen CC Cl H B ::.. :: Mechanism Elimination reaction Elimination, Bimolecular – E2

What Happens If There Is More Than One  -hydrogen ? ’’ Which one do we lose ? Elimination reaction Elimination, Bimolecular – E2

major product 81 % minor product 19 %  ’’  -H  ’ -H The major product is the one which has the lowest energy. 2-bromobutane 2-butene 1-butene Elimination reaction Elimination, Bimolecular – E2

Mechanism Concerted = only one step all bonds are broken and formed without the formation of any intermediates. strong base alkyl halide Elimination reaction Elimination, Bimolecular – E2

Mechanism Activated complex  Everything happens at once without any intermediates. Elimination, Bimolecular – E2 Elimination reaction

alkyl halide + strong base + heat = E2 alkyl halide + solvent + heat (solvolysis) = E1 alcohol + strong acid + heat = E1 (acid assisted) Only E1 reactions have rearrangements (carbocations) The most basic stuff Elimination reaction

Both reactions involve heating the R-X under reflux with KOH or NaOH 1)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 Vs Substitution R-X 2)Elimination R-X also undergo elimination reactions in the presence of sodium or potassium hydroxide. 2-bromopropane has reacted to give an alkene - propene

The very first pair of mechanisms and reactions which are commonly taught are the substitution and elimination reactions. All these can go by either a two-step mechanism (SN1 or E1) or one-step (SN2 or E2). So overall, you can find four possible mechanisms (SN2, SN1, E2 or E1,) along with combinations of mechanisms Elimination Vs Substitution R-X

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 favors elimination. Elimination Vs Substitution R-X 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

E1E2 Substrate Strong effect; reaction favored by tertiary halide Reactivity – primary Does not occurOccurs with strong base! Reactivity – tertiary Occurs under solvolysis conditions or with strong acids Highly favored when strong bases (OH -, OR - ) are used Reactivity – secondary Can occur in polar, protic solventsFavored when strong bases are used Solvent Very strong effect; reaction favored by polar, protic solvents Strong effect; reaction favored by polar, aprotic solvent Nucleophile/Base Weak effect; reaction favored by weak base Strong effect; reaction favored by strong base Leaving Group Strong effect; reaction favored by good leaving group Elimination reaction

H.W

The reactions in which the carbon skeleton of the molecule is rearranged to give a structural isomer of the original molecule. *These rearrangements can also be considered as a sequence of steps belonging to substitution, additions or elimination reactions. *involves a nucleophilic attack at electron deficient atoms e.g. C, O, N Usually in such reaction atoms or groups shift from one position to another within the molecule resulting in a new molecular structure.

e.g. Alkyl groups and hydrogen can migrate in rearrangement reactions to give more stable intermediate carbocations. 1. Rearrangement of Electron-Deficient Carbon 1° and 2° carbocations rearrange rapidly. Methyl shift Alkyl shift Hydride shift Rearrangement Reactions

Elimination SN1SN1 Methyl shift Rearrangement Reactions

Alkenes may rearrange to produce more highly substituted alkenes. Alkene Rearrangement Rearrangement Reactions

a carbocation Rearrangement Reactions transition state

Rearrangement Reactions

Carbocation Rearrangement Rearrangement Reactions

Carbocation Rearrangement

Rearrangement Reactions

 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. Hydrogen adds to carbon with fewer hydrogens. Halogen adds to carbon with most hydrogens. Anti-Markovnikov Reaction is initiated by peroxides or photochemically Free radical mechanism

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 species.Chain termination M ECHANISM O F T HE R EACTION Free radical reaction

Free Radical Addition of HBr: Peroxide

Gives an anti- Markovnikoff product BrCH 2 CHR2 BrCH 2 CHCHCH 2 Br RR Termination BrCH 2 CHR + BrCH 2 CHR Br Br.. Propagation +HBr BrCH 2 CHR H + BrCH 2 CHR + H 2 CCHRBrCH 2 CHR critical step Br. ROOR 2RO Initiation ROHBrROH+ + :Br :

WHY ANTI -MARKOVNIKOFF ? :Br... + H 2 CCHR BrCH 2 CHR.. Br CH 2 CHR FAVORED secondary primary BrCH 2 CHR 2 H 2 CCHR H+H+ CH 2 CHR H + CH 2 CHR + H secondary FAVORED CH 3 CHR Br IONIC FREE RADICAL Markovnikov Anti- Markovnikov Br adds first H adds first + Br - + H.

Stability Of Carbon Radical Intermediates Radicals are electron-deficient, just like carbocations, and have the same stability order. lowest energy highest energy tertiary secondaryprimary methyl and they are stabilized by resonance and / or hyperconjugation. etc. Free radical reaction

Solvents Radical reactions favor non-polar solvents when possible. Ionic reactions favor polar solvents. In the HBr reactions just mentioned in these slides, water is the solvent in both cases. However, in some of the other radical reactions, non-polar solvents are used. Free radical reaction

CH 4 + Cl 2 CH 3 Cl + CH 2 Cl 2 + CHCl 3 + CCl 4 + HCl hv Free radical reaction It is a very complicated free radical reaction

Free radical reaction

Information Enrichment Linkage with the life sciences

 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.

 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.

Find 3 different diseases caused by free radical reactions inside the body H.W