Pharmaceutical Organic Chemistry

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

2. WELCOME

3. 1-What is Benzene? 2-What is Electrophilic Substitution Reactions? 3- Addition reaction 4- Types of addition reaction 5-Mechanisms of substitution and addition reaction

4. Electrophilic Substitution Reactions

5. Benzene : Resonance Description Primary analysis revealed benzene had... a molecular mass of 78 amolecular formula of C6H6 Kekulé suggested that benzene was.. PLANAR and CYCLIC HadAlternating Double And Single Bonds Thus These Double Bonds Are Described As Conjugated Bonds.

6. Benzene : Resonance Description • However,all bond lengths in benzene to be equal and intermediate between single bond and double bond lengths (1.39 Å) and the ring is more stable than expected. • To explain the above, it was suggested that the structure oscillated between the two Kekulé forms but was represented by neither of them. It was a RESONANCE HYBRID( average of two structures that differ only in the placement of the valence electrons).

7. Benzene : Resonance Description * electron cloud delocalized all over the ring * the resonance picture this helps to explain lack of reactivity of benzene (substitution not addition ) Aromatic compounds are compounds that resemble benzene in chemical behavior thus they tend to react by substitution rather than by addition

8. Electrophilic Substitution Reactions • Electrophilic substitution happens in many of the reactions of compounds containing benzene rings – the arenes. • Benzene, C6H6, is a planar molecule containing a ring of six carbon atoms each with a hydrogen atom attached Resonance Energy = 36 Kcal / mole Kekule Structures All bonds are equivalent (The ring is symmetric. Bond lengths are between a single and a double bond) Very Stable (Less reactive than other groupings of atoms)

9. The “Double Bonds” in a Benzene Ring Do Not React Like Others Alkene Benzene no reaction + + no reaction + + no reaction + + no reaction + +

10. Reaction Mechanism All of the reactions follow the same pattern of mechanism. The Electrophilic substitution reaction takes place in this way: (+) restores ring resonance (+) :X intermediate benzenium ionor a benzenonium ion

11. The Nitration of Benzene Benzene is treated with a mixture of concentrated nitric acid and concentrated sulphuric acid at a temperature not exceeding 50°C. As temperature increases there is a greater chance of getting more than one nitro group, -NO2, substituted onto the ring. Nitrobenzene is formed. If you are going to substitute a -NO2 group into the ring, then the electrophile must be NO2+. This is called the "nitronium ion" or the "nitryl cation", and is formed by reaction between the nitric acid and sulphuric acid

12. The Halogenation of Benzene Benzene reacts with chlorine or bromine in an electrophilic substitution reaction, but only in the presence of a catalyst. The catalyst is either aluminium or ferric chloride (or aluminium (ferric) bromide if you are reacting benzene with bromine) or iron. FeCl3 As a chlorine molecule approaches the benzene ring, the delocalised electrons in the ring repel electrons in the chlorine-chlorine bond It is the slightly positive end of the chlorine molecule which acts as the electrophile. The presence of the ferric chloride helps this polarisation.

13. Friedel-Crafts Acylation of Benzene Named after Friedel and Crafts who discovered the reaction. • Reagent : normally the acyl halide (e.g. usually RCOCl) with aluminum trichloride, AlCl3, a Lewis acid catalyst. • The AlCl3 enhances the electrophilicity of the acyl halide by complexing with the halide. Electrophilic species : the acyl cation or acylium ion (i.e. RCO+ ) formed by the "removal" of the halide by the Lewis acid catalyst, which is stabilised by resonance as shown below.

14. Some Substitution Reactions of Benzene Halogenation + Friedel-Crafts Alkylation + Friedel-Crafts Acylation + - + + Nitration + - Sulfonation +

15. Addition Reactions

16. Addition Reaction • An addition reaction is a reaction in which two molecules join together to make a bigger one. Nothing is lost in the process. All the atoms in the original molecules are found in the bigger one. A+BAB • In an addition reaction, new groups X and Y are added to the starting material. A  bond is broken and two  bonds are formed. • Addition and elimination reactions are exactly opposite. A  bond is formed in elimination reactions, whereas a  bond is broken in addition reactions.

17. Addition Reaction The double bond dissolves back to single bond and new bonds reach out to A and B whose bond is also dissolving A-B can be :H-H H-OH H-X OH-OH OH-X

18. Addition Reaction Types of addition reactions 1) Electrophilic Addition (Reactions of Alkenes) 2) Nucleophilic Addition (aldehydes (RCHO) and ketones (RCOR)

19. Electrophilic Addition

20. Electrophilic Addition An electrophilic addition reaction is an addition reaction in which molecule has a region of high electron density is attacked by another molecule, atom or group carrying some degree of positive charge Electrophilic addition happens in many of the reactions of compounds containing carbon-carbon double bonds (the alkenes e.g. ethene). Electrophiles are strongly attracted to the exposed electrons in the π bond

21. Electrophilic Addition Addition of Hydrogen Halides Addition of HX (HI, HBr, HCl) H-X is polarized; H is +, X is - rates depend upon acid strength: stronger the acid, faster the rate HI > HBr > HCl>>>>>>>>HF Mechanism Step 2: Br- ion adds to carbocation Step 1: H+ adds to C=C double bond When the reaction forms the carbocation intermediate, the most highly substituted carbocation is favored : tertiary > secondary > primary

22. Electrophilic Addition Addition of Hydrogen Halides • Only one productis possible from the addition of these strong acids to symmetrical alkenes such as ethene, 2-butene and cyclohexene. • However, if the double bond carbon atoms are not structurally equivalent, i.e. unsymmetrical alkenesas in molecules of 1-propene, 1-butene, 2-methyl-2-butene and 1-methylcyclohexene, the reagent may add in two different ways to give two isomeric products. This is shown for 1-propene in the following equation.

23. Electrophilic Addition • However when the addition reactions to such unsymmetrical alkenes are carried out, it was found that 2-bromopropane is nearly the exclusive product. Thus it said the reaction proceeded according to Markovnikov’s rule Markovnikov’s rule stats that: In addition of unsymmetrical reagent to unsymmetrical alkenes the positive ionaddsto the carbon of the alkene that bears the greater number of hydrogen atoms and the negative ion adds to the other carbon of the alkene.

24. Mechanistic interpretation of Markovnikov’s rule: The reaction proceeds through the more stable carbocation intermediate.

25. Electrophilic Addition Addition of Hydrogen Halides • Addition of HCl to 1-Propene. • It is a regioselective reaction, follow Markovnikov`s rule. Regioselective: One of the possible products is formed in larger amounts than the other one(s). Regiospecific: Only one of the possible products is formed (100%). Anti-Markovnikov addition Addition of HBr to 1-Propene in presence of peroxide. In the presence of peroxides (chemicals containing the general structure ROOR'), HBr adds to a given alkene in an anti-Markovnikov fashion

26. Electrophilic Addition Addition of H2O: Hydration • Only one product is possible from the addition of H2O in presence of acids as catalysts to symmetrical alkenes such as ethene and cyclohexene. • However, addition reactions to unsymmetrical alkeneswill result in the formation of Markovonikov’s product preferentially.

27. ADDITION OF H2O HBr and HCl easily add to alkenes. Since water also is a molecule of the type HX which can donate a proton, H2O should be able to add to alkenes in the same way as HBr, for example, resulting in the hydration of an alkene. However, for the addition of H2O to alkenes to occur acid catalysts are required.

28. Nucleophilic Addition It is the most common reaction of aldehydes (RCHO) and ketones (RCOR) e.g. The reaction of aldehydes and ketones with hydrogen cyanide hydroxynitriles.

29. HW Classify each of the following as either substitution, elimination or addition reactions. a) b) c)

30. HW Draw the product of each of these examples of A-B when they add to 1-propene. H-H H-OH H-X OH-OH OH-X

31. Characteristics of Aromatic Compounds To be classified as aromatic, a compound must have 1-Cyclic structure 2-Coplanar structure. 3-Each atom of the ring must have a p orbital to form a delocalized π system i.e. no atoms in the ring can be sp3 hybridized instead all atoms must be sp2 hybridized (N.B. carbocation and carbanions are sp2 hybridized Conjugated (C=C-C=C-C=C) 4-Fulfill Huckel rule i.e. the system must have 4n + 2 pi electrons: thus by calculating n value it will be an integral number i.e. n=0, 1, 2, 3,

32. Examples Examples of aromatic compounds Examples of non aromatic compounds

33. Examples 10 6

34. a. IUPAC Names Nomenclature of Aromatic Compounds 1. MonosubstitutedBenzenes • They are named as derivatives of benzene. One side group is named as a prefix in front of the word benzene. • No number is needed for mono-substituted benzene.

35. Nomenclature of Aromatic Compounds • Benzene ring has priority over side chains with alkyl, alkoxy groups, halogens, double and triple bonds • In some cases the side chains on aromatic ring contain functional groups of higher priorities (NH2, OH, CHO,C=O, COOH, COOR) thus in this case the aromatic ring will be considered as a substituent and the side chain will be used to give the root name. Two aromatic radials are known.

36. Nomenclature of Aromatic Compounds b. Common Names of Monosubstituted Benzenes

37. Nomenclature of Aromatic Compounds 2.Nomenclature of Disubstituted and polysubstituted Benzenes • All disubstituted benzenes (two groups are attached to benzene), can give rise to three possible positional isomers. • When the substituents are different, they are of equal priorities they should be listed in alphabetical order.

38. Nomenclature of Aromatic Compounds • If one of the substituents is part of a parent compound, then the di-substituted or poly-substituted benzene is named as a derivative of that parent compound i.e. priorities determine the root name and substituents.

39. 1-Electrophilic Aromatic Substitution Reactions Reactions of Aromatic

41. Reactions of Aromatic compounds • Alkyl groups and groups with lone pairs (electron donating groups) direct new groups to ortho-, para-positions and speed-up the reaction (i.e. o & p directors andactivating groups). • Halogens direct new groups to ortho-, para- positions but they slow down the reaction (i.e. halogens are o & p directors and deactivating groups). Electron withdrawing groups such as nitro, nitrile, and carbonyl direct new groups to the meta-position and slow the reaction down (i.e. i.e. m directorsanddeactivating groups). • Thus the order of reactivity of benzene and monosubstituted benzene derivatives in E.Ar.sub. is as in the following chart. Substituted benzene with o,p directors > Benzene > Halobenzene derivatives > Substituted benzene with m- directors

42. Reactions of Aromatic 2-Side-Chain Reactions of Aromatic Compounds 1)Halogenation a) alkyl side chain(usingUV) Or b) Substituted benzene (with CCl4, AlCl3,FeCl3 (two products)

43. Reactions of Aromatic 2. Nitration

44. Reactions of Aromatic 3.Oxidation

45. Q1: What is the empirical formula of the following compound: (p-methyl-Toluene): Q2: What is the final product of the following reaction? a) o-chlorobenzaldehyde b) m-chlorobenzaldehyde c) p-chlorobenzaldehyde d) a,c Q3:Which one of the following compounds has aromatic character?

46. Thank You for your kind attention !