PCH 301 Organic Pharmaceutical Chemistry PDF

PCH 301: ORGANIC PHARMACEUTICAL CHEMISTRY TOPIC: ORGANIC REACTIONS AND MECHANISMS 1 ADDITION REACTION 2 TRODUCTION Addition Reactions are chemical reactions where sma molecules are added to compounds to form adducts Occur in compo...

PCH 301: ORGANIC PHARMACEUTICAL CHEMISTRY TOPIC: ORGANIC REACTIONS AND MECHANISMS 1 ADDITION REACTION 2 TRODUCTION Addition Reactions are chemical reactions where sma molecules are added to compounds to form adducts Occur in compounds having π electrons Product contains all elements of the two reacting species Addition Reactions Electrophilic Nucleophilic Addition Addition Reactions Reactions Carbon-carbon double bond, C=C Carbon-hetero atom double bond, C=O, C 3 Carbon-carbon triple bond, C≡C Carbon-hetero atom triple bond, C≡N Electrophilic Addition Reactions What does it mean? An electrophile accepts electron pair from double or triple bonds to form carbocation intermediate, and thereafter, nucleophile attacks on positive species to form addition product Addition C C + E-Nu C C Reagent Substrate/Alkene Nu E Product 4 General reaction mechanism: Step 1: Slow C C + E-Nu C C + Nu E Step 2: Fast C C C C E Nu E Product Nu 5 e electrophile, having some positive aracter, is attracted to the alkene. ctrons in the pi bond form a nd with the positive end. carbocation is formed. The species at is left now has a lone pair. acts as nucleophile and attacks e carbocation using its lone pair form a covalent bond 6  Ethers Halogenoa es id Ke al to lh n es ky Alkene Al kanes l s Variety Electrophilic addition of other Aldehydes Leads to conversion/ function Alkyl dihalides Alkyneinterconversion al s groups ls Al ho ka Cycloalkane co n Al es 7  Hydrogenation of Alkenes and Alkynes ydrogenation of alkenes and alkynes lead to the formation of alkanes takes place in the presence of a metal catalyst, e.g Pt, Pd or Ni is a reduction reaction he two new C—H σ bonds are formed simultaneously from H atoms. So, the catalytic hydrogenation is stereospecific, giving only the syn addition product. Examples of catalytic hydrogenation reaction leading to the interconversion of alkenes and alkynes to produce alkanes are shown below. Mechanism of reaction is described 8 9 10 philic addition to symmetrical and unsymmetrical π bonds ymmetrical alkenes/alkynes have Unsymmetrical means different he same substituents at each end substituents are at each end of f the double/triple bond. the double/triple bond. 11 nd below two possible mechanisms in the electrophilic addition o symmetrical alkene. his shows addition of HBr to 2,3-dimethyl-2-butene. the mechanism shown, the π electrons of the alkene provide he electrons for a new bond between the right-hand carbon and hydrogen. They could equally well have been used to form a bond between the left-hand carbon and hydrogen. 12 ectrophilic addition of unsymmetrical reagents to unsymmetrical ouble or triple bonds can result in two different products. ese products are not formed in equal amounts. is kind of addition reaction follows Markovnikov’s rule. cording to Markovnikov’s rule, addition of unsymmetrical reagents,.g. HX, H2O or ROH, to an unsymmetrical alkene proceeds in a way that the hydrogen atom adds to the carbon that already has the most hydrogen atoms. arkovnikov rule states that, in the ionic addition of an unsymmetrical eagent to a double bond, the positive portion of the adding reagent dds to a carbon atom of the double bond to yield the more stable arbocation intermediate. is addition to unsymmetrical π bonds produces regioselective produc 13  Product I Product II R R R R R R C C + HX R C C H R C C H R H X H H X Unsymmetrical alkene Markovnikov addition AntiMarkovnikov addition Carbocation leading to product I Carbocation leading to product II R R R R More stable R C C H R C C H carbocation H H Three alkyl group attached Two alkyl group attached to the positive center to the positive center 14 arbocation stabilization Carbocations, positively charged species, are inherently reactive and unstable. The more unstable they are, the less easily they are formed and the less likely the overall reaction. Any factor which helps to stabilize the positive charge will make the reaction more likely. There are three ways in which a positive charge can be stabilized: inductive effects, hyperconjugation, and delocalization. Inductive effects- Alkyl groups can donate electrons towards a neighboring positive center and this helps to stabilize the ion. 15  30 CH3 0 2 CH3 10 H H H3C C > H C > H C > H C CH3 CH3 CH3 H Methyl Hyperconjugation- involves the overlap of the vacant 2p orbital of the carbocation with a neighboring C-H σ- bond orbital. The more substituents present, the more chancesVacant are2pfor hyperconjugation. orbital H H R R C C = C C R R R R R R 16  CH3 LRT: which of the two species, A and B, OH is more stable? Give reason. C C A B Delocalization- distribution of electron density beyond a fixed place such as a single atom, lone pair, or covalent bond. Allyl and benzyl carbocations are more stable than alkyl carbocations, because their unpaired electrons are delocalized. I II Electron delocalization increases the stability of a molecule. LRT: identify species I to IV here in their order of stabilities and justify your answer with N III H reasons. IV 17 alogenation of Alkenes and Alkynes Halogenation is the addition of dihalide, Cl2 or Br2, across the double bond in an alkene to yield a vicinal dihalide. This reaction is used as a test for unsaturation (π bonds), because the red colour of the bromine reagent disappears when an alkene or alkyne is present. The halides add to neighboring carbons from opposite faces of the molecule. The reaction occurs in the presence of inert and non- nucleophilic solvents, such as methylene chloride, chloroform, or carbon tetrachloride 18 Mechanism: 19 drohalogenation of Alkenes and Alkynes lkenes are converted to alkyl halides by addition of HX (X= Cl, Br or I) ddition of HX to unsymmetrical alkenes follows Markovnikov’s rule. he reaction is regioselective, and occurs via the most stable arbocation intermediate. CH3 Br H2C CH + HBr CH3CHCH3 + CH3CH2CH2Br Propene 2-Bromopropane 1-Bromopropane (Major product) (Minor product) Mechanism: 20 carbocation interm. H CH3 H H C C + H Br H3C C CH3 H3C C CH3 H H Br Br 2-Bromopropane 20 ydration of Alkenes and Alkynes The hydration reaction occur when alkenes are treated with aq. acids, most commonly H2SO4, to form alcohols. This is called acid-catalysed hydration of alkenes. Addition of water to an unsymmetrical alkene follows Markovnikov’s rule. CH H2SO4 3 CH3 The reaction is highly regiospecific. H C C CH + HO 3 2 2 H3C C CH3 2-Methylpropene OH Mechanism: (Isobutylene) t-Butyl alcohol CH3 CH3 (Major product) H2O H3C C CH2 + H OSO3H H3C C CH3 + HSO4- H2 O CH3 CH3 H2SO4 + H3C C CH3 H3C C CH3 OH H O H 21 HSO4- ddition of alcohols to alkenes yield ethers in acid catalysed reaction. ddition of alcohol to an unsymmetrical alkenes follows Markovnikov’s rule. CH3 H3C H H2SO4 + CH3OH H3C C CH3 H3C H OMe 2-Methylpropene Methyl t-butyl ether Mechanism: H3C O H HSO4- H H3C H3C H C CH3 H3C C CH3 CH3OH H3C H H3C CH3 H3C O H3C C CH3 CH3 22 Nucleophilic Addition Reactions In nucleophilic addition reaction a nucleophile attacks on the electron deficient double bond to form anion intermediate. Then second step is protonation of anion to form addition product.  Reasons for carbonyl compounds to undergo nucleophilic addition reactions: Oxygen (3.44) is more electronegative than carbon (2.55) Since the carbonyl carbon holds a partial positive charge, it behaves as an electrophile. The partial negative charge on the oxygen atom can be stabilized via the introduction of an acidic group. The proton donated by the acid bonds with the carbonyl oxygen atom and neutralizes the negative charge. 24  s Alkene Ke in & es to a m es n es En in Aldeh Im ydes Nucleophilic addition Variety Diol of other Hydrazones & Leads to conversion/ Semicarbazone Ketoninterconversion s function al group es & ls Ca id 3 0 , 2 ho ac rb Cyanohydrin 1 0 co 0 ox Al yl ic 25  Nu is negatively charged O O OH H3O+ anion, e.g. HO-, RO- & H-. R C Y R C Y R C Y Readily attacks the carbonyl Nu carbon, and forms alkoxide Nu Nu Alkoxide intermediate Alcohol interm. Which is subsequently Y= H or R protonated by aq. acid Nu is neutral molecule with a O H+ OH OH lone pair of electrons, e.g. H2O or R C Y R C Y R C Y alcohol. Requires an acid catalyst, the carbonyl oxygen is Y= H or R Nu Nu Alcohol protonated by acid, Which is increases the susceptibility of the carbonyl carbon to Nu attack OH O H2 R C Y Dry H+ Attacking nucleophile has R C Y R C Y + H2O a pair of nonbonding Nu Nu Nu electrons available in the Y= H or R Nu = ROH, RNH2 addition product 26 on of organometallic reagents to carbonyl compounds dehydes and ketones react with organometallic agents to yield different classes of alcohols O OMgBr OMgBr CH3 O CH3MgBr H3O+ CH3MgBr + H3O H C H H C H CH3CH2OH H3C C H H3C C H CH3CHOH Dry ether Dry ether Formaldehyde CH3 Ethanol Acetaldehyde 2-Propanol CH3 (10 Alcohol) (20 Alcohol) Mechanism: O OMgBr CH3 CH3MgBr + H3O H3C C CH3 H3C C CH3 H3C C OH O OMgBr OH H Dry ether Dry ether H3O+ Acetone CH3 CH3 H C H H C H H C H tert-Butanol CH3 CH3 (30 Alcohol) H3C MgBr 27 rbonation of Grignard reagent gnard reagent reacts with CO2 to give magnesium salts of carboxylic dition of aqueous acid yields carboxylic acid. O O CO2 H3O+ CH3CH2 MgBr CH3CH2 C OMgBr CH3CH2 C OH Gridnard reagent Propanoic acid O O C O CH3CH2 C O CH3CH2 MgBr H3O+ O CH3CH2 C OH Propanoic acid 28 on of ammonia and its derivatives to carbonyl compounds mary amines, hydroxylamine, hydrazine and semicarbazide, react ith aldehydes and ketones in the presence of an acid catalyst generate imines or substituted imines. H2N OH N OH Imines are nucleophilic and basic. R C Y Dry H+ Oxime The formation of all imines follows the R'NH2 N R ' same mechanism. R C Y In aqueous acidic solution, imines are + Dry H Imine (Schiff's base) O N NH hydrolysed back to the present aldehyd R C Y NH2NH2 2 R C Y and ketones, and amines. Y= H or R Dry H+ Hydrazone N NHCONH2 NH2NHCONH2 R C Y + Dry H Semicarbazone 29  O O OH OH2 H + Dry H+ H3C C H H3C C H H3C C H H3C C H + H3O NHCH2CH3 NHCH2CH3 NHCH2CH3 CH3CH2NH2 H Neutral carbinolamine NCH2CH3 H3O+ + H3C C H H3C C H H2O + Imine H N CH2CH3 (Schiff's base) 30 Practice questions 1. Define the terms electrophilic and nucleophilic addition reactions. 2. Explain why electrophilic addition reaction takes place in the Carbon-carbon double or triple bonds, while nucleophilic addition reaction takes place in the carbon- hetero atom double or triple bond. 3. Electrophilic addition of unsymmetrical reagents to unsymmetrical double bonds is said to follow Markovnikov’s rule. State the Markovnikov’s rule. 4. Show in the reaction below the Markovnikov addition leading CH H3C to product I and anti-Markovnikov addition leading to product3 II. Product I Product II C C + HBr (Markovnikov addition) (Anti-Markovnikov addition) H3C H 31 5. List and explain briefly the three factors that lead to carbocation stabilization. 6. The reaction of propene with HBr shown below, gives 2-Bromopropane as a major product. Provide the mechanism of this reaction. CH3 Br H2C CH + HBr CH3CHCH3 + CH3CH2CH2Br Propene 2-Bromopropane 1-Bromopropane (Major product) (Minor product) 7. Hydration of 2-methyl propene gives t-Butyl alcohol as shown below. Show the mechanism of the reaction. CH3 CH3 H2SO4 H3C C CH2 + H2O H3C C CH3 2-Methylpropene OH (Isobutylene) t-Butyl alcohol (Major product) 32 ELIMINATION REACTION 1,2-ELIMINATION OR β-ELIMINATION 33 What does the term mean? Electronegative atom or a leaving group being removed along with a hydrogen atom from adjacent carbons in the presence of strong acids or strong bases and high temperatures. Alky Alcohols halides Dehydrati Dehydrohalogena on tion (-H2O) (-HX) Alken es It is the reverse of electrophilic addition of H2O and HX to alkenes 34  β Carbon α Carbon Conc. H2SO4 CH3CH2OH H2C CH2 + H2O Heat Ethyl alcohol Ethylene Alcoholic KOH CH3CH2Cl H2C CH2 + HCl Heat Ethyl chloride Ethylene The atoms are removed from the adjacent carbon. Also called β-elimination because a proton is removed from a β-carbon. 35 1 reaction or first order elimination CH3 CH3 CH3 H3C CH3OH H C C C2H5 + HBr + CH3OH Heat H Br H C2H5 3-Bromo-3-methyl pentane 3-Methyl-2-pentene E1 reaction results from the loss of a leavi group to form a carbocation intermediate, followed by the removal of a proton to form CH3 CH3 CH3 CH3 the C=C bond. H C C C2H5 Slow H C C C2H5 + This Br reaction is common with good leaving H Br H Groups, stable carbocation and weak base H3C OH Fast (strong acids). CH3 Unimolecular H3C + CH3OH2 + Br reaction H C2H5 10 and 20 alkyl halides do not usually react with this 36 mechanism. reaction or second order elimination CH3 CH3 CH3 H3C CH3ONa H C C C2H5 + CH3OH + NaCl CH3OH, heat H Cl H C2H5 E2 reaction takes place through the 3-Chloro-3-methyl pentane 3-Methyl-2-pentene removal of a proton and simultaneous loss CH3 CH3 of a leaving group to form the C=C H3C CH3 H C C C2H5 Fast bond. H This reaction is common with high Cl H C2H5 concentration of strong bases + CH3ONa (weak acids), poor leaving groups CH3OH + NaCl and less stable carbocations. Bimolecular reaction E2 reaction is the most effective for the synth of alkenes from 10 alkyl halides. 37 ehydration of alcohols OH H2SO4, heat CH3CH2 CHCH3 CH3CH CHCH3 + CH3CH2CH CH2 2-Butanol H2O (E)-2-Butene (Z)-1-Butene (Major product) (Minor product) Mechanism: H OH H O Heat CH3CH2 CHCH3 + H O SO3H CH3CH2CHCH3 + HSO4- H2SO4 + CH3CH CHCH3 CH3CH CHCH3 + H2O H + HSO4- 38  CH3 OH CH3 H2SO4 H3C H3C C C CH3 + H2O + H2SO4 Heat H3C CH3 H CH3 2,3-Dimethylbut-2-ol 2,3-Dimethylbutene The dehydration of 2,3-dimethylbut-2-ol gives predominantly 2,3-dimethylbutane Mechanism: via E1 reaction. H H CH3 O CH3 OH + H O SO3H H3C C C CH3 + HSO4- H3C C C CH3 H CH3 H CH3 Dehydration of 20 and 30 alcohols involves formation of carbocation H3C CH3 CH3 intermediate, thus making them E H3C C C CH3 + H O H2SO4 + H3C CH3 reaction. 2 H CH3 HSO4- 39  H2SO4, heat CH3CH2CH2OH CH3CH CH2 Propanol H2O Propene But dehydration of 10 alcohols is an E2 reaction since formation of a Mechanism: H primary carbocation is rather O H difficult and unstable. CH3CH2CH2OH + H O SO3H CH3CH CH2 H + HSO4- CH3CH CH2 + H2O + H2SO4 40 hydrohalogenation of alkyl halides kenes can be produced by dehydrohalogenation of alkyl halides a either E1 or E2 reaction mechanism. e E1 reaction involves the formation of a planar carbocation ntermediate. th syn and anti elimination can occur. pending on the substrates, E1 reaction forms a mixture of cis (Z) and ans (E) products. CH3 CH3 CH3 C2H5OH H3C C Br H3C C CH2 + H3C C OC2H5 Heat CH3 2-Methylpropene CH3 t-Butyl bromide (E1 Major product) Ethyl t-Butyl ether (SN1 minor product) 41  Mechanism: CH3 E2 elimination is stereospecific, a CH 3 H C 3 C Br Slow H C 3C + Br it requires an antiperiplanar (180 CH 3 CH 3 arrangement of the groups being eliminated. E2 reaction mostly forms one CH 3 CH 3 Fast CH + CH OH H C 3 C HC C3 2 3 2 CH product since only anti eliminati 2 H can take place. CH OH 3 The elimination reaction may Dehydrohalogenation of 20 and 30 generate alkenes that are alkyl halides undergoes both E1 andconstitutionalE2 isomers in regio- reactions. selective fashion. 10 alkyl halides can not undergo Elimination often favour the more E1 reactions due to difficulty of forming stable trans-product over the cis primary carbocations, so undergo only product- stereoselectivity. E2 reactions. 42  C2H5ONa CH3 CH3 CH3CH2CH2 Br CH3CH CH2 KOH + H2O + KBr EtOH, heat H3C C Br H3C C CH2 Heat + C2H5OH + NaBr CH3 2-Methylpropene t-Butyl bromide (>90%) Mechanism: CH3 EtOH H CH CH2 Br CH3CH CH2 The E2 elimination can be a good + C2H5OH + synthetic method for the preparation NaBr C2H5ONa of alkene when 30 alkyl halide and a strong base is used. 43 Practice questions 1. Explain the term first and second order elimination reactions. 2. Give the mechanism of reaction that lead to the synthesisCH3of CH33-methyl-2-pentene CH ONa H3C CH3 in the reaction below 3 H C C C2H5 + CH3OH + NaCl CH3OH, heat H Cl H C2H5 3-Chloro-3-methyl pentane 3-Methyl-2-pentene 3. The dehydration of 2-Butanol gives predominantly (E)- 2-butene. OH Show the mechanism of the reaction. H2SO4, heat CH3CH2 CHCH3 CH3CH CHCH3 + CH3CH2CH CH2 2-Butanol H2O (E)-2-Butene (Z)-1-Butene (Major product) (Minor product) 44