Pharmaceutical Organic Chemistry-1 Past Paper PDF 3-Nov-24

Pharmaceutical Organic Chemistry-1 3-Nov-24 By: Marwa Ehab Abdelaziz, PhD Lecturer of Pharmaceutical Chemistry Facult...

Pharmaceutical Organic Chemistry-1 3-Nov-24 By: Marwa Ehab Abdelaziz, PhD Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy Alexandria University [email protected] 1 1 Alkyl Halides Alkyl halides: a halogen atom is bonded to an sp3-hybridized carbon. CH2Cl2 CHCl3 CH3I 2 2 Dr Marwa Ehab 1  Pharmaceutical Organic Chemistry-1 3-Nov-24 Classification Alkyl Halide Primary Secondary Tertiary Alkyl Halides Alkyl Halide Alkyl Halide 3 3 Alkyl Halides Nomenclature Preparation Reactions 4 4 Dr Marwa Ehab 2  Pharmaceutical Organic Chemistry-1 3-Nov-24 Nomenclature 1) Monohalogen derivatives: The common name of alkyl halides is the name of the alkyl group plus the stem of the name of the halogen, with the ending -ide. CH3 CH 2 I CH3CH2CH2Cl Ethyl iodide N-Propyl chloride Benzyl bromide 5 5 Nomenclature 1) Monohalogen derivatives: The IUPAC system uses the name of the parent alkane with a prefix indicating the halogen substituents, preceded by number indicating the substituent’s location. The prefixes are fluoro-, chloro-, bromo-, and iodo-. 6 6 Dr Marwa Ehab 3  Pharmaceutical Organic Chemistry-1 3-Nov-24 Nomenclature 2) Dihalogen derivatives: Dihalogen Derivatives Geminal Vicinal Dihalides Dihalides 7 7 Preparation of alkyl halides 1. From alkanes 2. From alkenes 3. From alkynes 4. From alcohols 8 8 Dr Marwa Ehab 4  Pharmaceutical Organic Chemistry-1 3-Nov-24 Preparation of alkyl halides I- From Hydrocarbons: Free radical halogenation of alkanes is the substitution of a single hydrogen on the alkane for a single halogen to form a haloalkane. Light is required to initiate the radical formation. h  CH4 H3C Cl (Free radical mechanism) Cl2 9 9 Preparation of alkyl halides II- From Alkenes: 10 10 Dr Marwa Ehab 5  Pharmaceutical Organic Chemistry-1 3-Nov-24 Preparation of alkyl halides III- From Alkynes: 11 11 Preparation of alkyl halides IV- From Alcohols: The sulfur dichloride oxide (thionyl chloride) reacts with alcohols at room temperature to produce a chloroalkane. This reaction works best for primary and secondary alcohols. The advantage that this reaction is that the two other products of the reaction (sulfur dioxide and HCl) are both gases. That means that they separate themselves from the reaction mixture. ROH + SOCl2 RCl + SO2 + HCl 12 12 Dr Marwa Ehab 6  Pharmaceutical Organic Chemistry-1 3-Nov-24 Reactions of alkyl halides I- Nucleophilic substitution reaction: 1. Bimolecular nucleophilic substitution reaction (SN2) 2. Unimolecular nucleophilic substitution reaction (SN1) II- Elimination reaction: 1. Bimolecular Elimination Reaction (E2) 2. Unimolecular Elimination Reaction (E1) 13 13 Reactions of alkyl halides I- Nucleophilic substitution reaction: The alkyl halide forms a new bond with the nucleophile which substitutes for (replaces) the halogen at the alpha-carbon. The halogen must leave and is called the "Leaving Group". 14 14 Dr Marwa Ehab 7  Pharmaceutical Organic Chemistry-1 3-Nov-24 Reactions of alkyl halides I- Nucleophilic substitution reaction: 1. Bimolecular nucleophilic substitution reaction (SN2) 15 15 Reactions of alkyl halides I- Nucleophilic substitution reaction: 1. Bimolecular nucleophilic substitution reaction (SN2) In an SN2 reaction, the nucleophile attacks from the back side. This attack causes a change in the configuration (inversion of configuration) of the carbon atom that is the target of nucleophilic attack 16 16 Dr Marwa Ehab 8  Pharmaceutical Organic Chemistry-1 3-Nov-24 Reactions of alkyl halides I- Nucleophilic substitution reaction: 1. Bimolecular nucleophilic substitution reaction (SN2) 17 17 Reactions of alkyl halides I- Nucleophilic substitution reaction: 2. Unimolecular nucleophilic substitution reaction (SN1) (Transition state) 18 18 Dr Marwa Ehab 9  Pharmaceutical Organic Chemistry-1 3-Nov-24 Reactions of alkyl halides I- Nucleophilic substitution reaction: 2. Unimolecular nucleophilic substitution reaction (SN1) Slow RX R + X Fast Nu Nu-R 19 19 Reactions of alkyl halides I- Nucleophilic substitution reaction: 2. Unimolecular nucleophilic substitution reaction (SN1) CH3 CH3 e.g. H3C C Br H2O H3C C OH CH3 CH3 Mech. CH3 b a H3C complete C Br C ionization sp2 H3C sp3c H3C CH3 H3C planar Nu attack from both sides rom b) att ack f front ack from CH3 a) att side side H3C Nu C back C Nu CH3 H3C CH3 H3C 50 % 50 % 20 20 Dr Marwa Ehab 10  Pharmaceutical Organic Chemistry-1 3-Nov-24 Br H2O OH e.g. H3CH2CH2C C CH2CH3 H3CH2CH2C C CH2CH3 CH3 CH3 (R)-3-bromo-3-methylhexane 50 % (R)-3-hydroxy-3-methylhexane 50 % (S)-3-hydroxy-3-methylhexane Mech. CH3 Et b a H3C Br CH3 C Br C H3CH2CH2C sp3c H3CH2CH2C sp2 CH2CH3 Pr H3CH2C planar H2O attack from both sides r om b) at ack f front tack from a) att side side bac k CH3 H3C HO C C OH CH2CH2CH3 H3CH2CH2C CH2CH3 CH2CH3 50 % (S) 50 % (R) 21 Racemic modification 21 Examples of nucleophilic substitution reaction 22 22 Dr Marwa Ehab 11  Pharmaceutical Organic Chemistry-1 3-Nov-24 Factors affecting nucleophilic substitution reaction (SN2 &SN1) 1. Structure of alkyl halide 2. Solvent 3. Nature of the nucleophile 4. Leaving groups 23 23 Factors affecting nucleophilic substitution reaction 1- Structure of alkyl halide: SN2 mechanism Simple alkyl halides show the following general order of reactivity in SN2 reactions 24 24 Dr Marwa Ehab 12  Pharmaceutical Organic Chemistry-1 3-Nov-24 Factors affecting nucleophilic substitution reaction 1- Structure of alkyl halide: SN1 mechanism The primary factor that determines the reactivity of organic substrates in an SN1 reaction is the relative stability of the carbocation that is formed. Slow RX R + X Fast Nu Nu-R 25 25 Examples SN2 SN1 26 26 Dr Marwa Ehab 13  Pharmaceutical Organic Chemistry-1 3-Nov-24 Benzylic and allylic halides are 1ry alkyl halides and undergo both SN1 and SN2 by the same reaction rate. Benzyl halide Allyl halide Resonance 27 27 Aryl or vinyl halides do NOT undergo nucleophilic substitution; neither SN1 nor SN2 as: The halide is strongly bonded and do NOT form carbocation easily. Overlapping P orbitals that form the π-bonds in vinyl and aryl halides completely block the access of a nucleophile to the back side of the α carbon 28 28 Dr Marwa Ehab 14  Pharmaceutical Organic Chemistry-1 3-Nov-24 Factors affecting nucleophilic substitution reaction 2- Solvent: Solvent Non polar e.g. benzene Polar Polar protic Polar aprotic e.g. H2O, ROH, e.g. DMF HCON(CH3)2 CH3COOH DMSO (CH3)2SO Polar protic solvents have a hydrogen atom Polar aprotic hydrogen is attached to an electronegative atom not highly polarized (Solvate both cation and anion) 29 29 Factors affecting nucleophilic substitution reaction 2- Solvent: SN2 reactions take place much more rapidly in polar aprotic solvents. In polar aprotic solvents the nucleophile is only very slightly solvated and is, consequently, highly reactive, while, molecules of polar protic solvents form hydrogen bonds with nucleophile. Polar aprotic solvents solvate cations very well and is, consequently, increase nucleophile reactivity. 30 Dr Marwa Ehab 15  Pharmaceutical Organic Chemistry-1 3-Nov-24 Factors affecting nucleophilic substitution reaction 2- Solvent: In SN1 reaction polar protic solvent will greatly increase the rate of ionization of an alkyl halide. 1) Polar protic solvents solvate cations and anions effectively. 2) Solvation stabilizes the transition state leading to the intermediate carbocation and halide ion more it does the reactants Water is the most effective solvent for promoting ionization O H H H O H2O OH2 O H H H X H2O H3C OH2 H OH2 O H H O H Polar aprotic solvents are not used in SN1 reactions because some of them can react with the carbocation intermediate and give you an unwanted product. 31 Factors affecting nucleophilic substitution reaction 2- Solvent: SN2 reactions SN1 reactions polar aprotic polar protic solvents DMF, solvents DMSO H2O, ROH, CH3COOH 32 Dr Marwa Ehab 16  Pharmaceutical Organic Chemistry-1 3-Nov-24 33 33 Dr Marwa Ehab 17