Pharmaceutical Organic Chemistry

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

2. WELCOME

3. 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

4. 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 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 An elimination reaction is one where starting material loses the elements of a small molecule such as HCl or H2O or Cl2 during the course of the reaction to form the product.

5. Elimination reaction 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 Types of Elimination reactions • Elimination, Unimolecular - E1 • Elimination, Bimolecular - E2

6. Elimination reaction Elimination, Unimolecular - E1

7. Elimination reaction Elimination, Unimolecular - E1 I) Dehydrohalogenation (-HX) of alkyl halides • The mechanism is similar to theSN1 reactionexcept the second step involves a proton abstraction and πbond formation instead of a substitution. • 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 βhydrogen off to produce the most stable alkene according to the Zeitsev Rule.

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

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

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

11. Elimination reaction Elimination, Unimolecular - E1 II) Dehydration of alcohols Elimination of H2O from an alcohol using acid . H2SO4 or H3PO4 R-OH + H2O R-R ∆ alcohol alkene acid catalyst The dehydration reaction is acid-catalyzed.

12. Elimination reaction Elimination, Unimolecular - E1 Mechanism of Dehydration alcohol acidcatalyst protonatedalcohol acidcatalyst alkene carbocation

13. Elimination reaction 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

14. Elimination reaction Elimination, Unimolecular - E1 When The E1 Mechanism Occurs? 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.

15. Elimination reaction Elimination, Bimolecular – E2

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

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

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

19. Elimination reaction Elimination, Bimolecular – E2 Mechanism The Base Takes The b-hydrogen B: B H H C C C C C l : : .. .. C l : : ..

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

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

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

23. Elimination reaction Elimination, Bimolecular – E2 d- Mechanism Activated complex d- Everything happens at once without any intermediates.

24. Elimination reaction The most basic stuff 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)

25. Elimination Vs Substitution R-X 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. 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

26. Elimination Vs Substitution R-X 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

27. 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 What you get most of depends on a number of factors. 1. The type of halogenoalkaneThis is the most important factor. 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.

28. Elimination reaction

31. H.W

32. Rearrangement Reactions 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.

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

34. Rearrangement Reactions Methyl shift SN1 Elimination

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

36. Carbocation Rearrangement Rearrangement Reactions a carbocation transition state

37. Carbocation Rearrangement Rearrangement Reactions

38. Rearrangement Reactions Carbocation Rearrangement

39. Rearrangement Reactions Carbocation Rearrangement

40. Rearrangement Reactions Carbocation Rearrangement

41. Rearrangement Reactions

42. Rearrangement Reactions

43. 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. 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

44. Free radical reaction 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.

45. Free radical reaction Free Radical Addition of HBr: Peroxide

46. Gives an anti- Markovnikoff product Initiation .. .. .. . 2 R O R O O R .. .. .. .. .. .. .. . . :Br : R O H B r R O H + + .. .. .. .. Propagation . . Br H C C H R B r C H C H R + 2 2 . B r C H C H R + H B r 2 H . Br B r C H C H R + critical step 2 B r . Termination . Br B r C H C H R + B r C H C H R 2 2 . B r C H C H C H C H B r 2 B r C H C H R 2 2 2 R R

47. B r C H C H R 2 2 B r C H C H R .. 2 . :Br .. . C H C H R 2 B r + C H C H R 2 H H C C H R + 2 C H C H R H 2 WHY ANTI -MARKOVNIKOFF ? Anti- Markovnikov FREE RADICAL + H. . Br adds first FAVORED secondary H C C H R + 2 primary IONIC H adds first primary secondary FAVORED H+ + Br- C H C H R 3 Markovnikov Br

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

49. 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.

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