1.SUBMITTED TO:Ms. S.D. VachalaDept of Pharmaceutical ChemistyM.C.O.P.S. Manipal SUBMITTED BY: DEPARTMENT OFPHARMACEUTICAL Shikha TyagiCHEMISTRYM. PHARM- IMCOPS MANIPAL100602017 Dept of Pharm. Chem.M.C.O.P.S. Manipal

2. Contents1 Addition to carbon carbon multiple bondElectrophilic additionNucleophilic additionFree radical reactionOrientationReactivityReactions2 Addition to carbon hetero bondAdditionAddition toAddition toAddition to 3. Addition to CarbonCarbon Multiple Bonds Electrophilic Nucleophilic Free radical 4. Electrophilic additionMechanismStep1Step2 5. Electrophile can be:- A positive ion. The positive end of a dipole or an induced dipole, with the negative part breaking off either during the first step or shortly after..Addition to a double bondThere are thus three possibilities.Both Y and W may enter from the same side of the plane, in which case the addition is stereospecific and Syn.They may enter from opposite sides for stereospecific anti addition.The reaction may be nonstereospecific. 6. stereospecificityOn double bondreactant addition productcisSynErythrocisAnti ThreotransSynThreotransAnti ErythroOn triple bondSyn gives cis olefinAnti gives trans olefins 7. ReactionssynAnti 8. Nucleophilic AdditionStep 1step2 9. Free-Radical AdditionInitiation Propagation Termination 10. ReactivityElectrophilic addition:-Electron-donating groups increase the reactivity of a double bond toward electrophilic additionelectron-withdrawing groups decrease reactivity .The reactivity toward electrophilic addition of a group of alkenes increased in the order :-Nucleophilic addition:-The situation is reversed. 11. SOME IMPORTANT FACTSComparison between double and triple bonds. There is a higher concentration ofelectrons between the carbons of a triple bond than in a double bond, and yet triplebonds are less subject to attack at an electrophilic site and more subject to nucleophilicattack than double bonds.This statement is not universally true, but it does hold in most cases. In compoundscontaining both double and triple bonds (nonconjugated), bromine, an electrophilicreagent, always adds to the double bond. In fact, all reagents that form bridgedintermediates react faster with double than with triple bonds.EXPLANATION TO THE FACT:As mentioned, it is true that in general triple bonds are more susceptible to nucleophilicand less to attack on an electrophilic site than double bonds, in spite of their higherelectron density.Because:-The electrons in the triple bond are held more tightly because of the smaller carboncarbon distance; it is thus harder for an attacking electrophile to pull out a pair.The availability of the unfilled orbital in the alkyne. 12. OrientationFor electrophilic attack, the answer is given byMarkovnikovs rule: The positive portion of the reagent goes to the side of the doubleor triple bond thathas more hydrogens.Why does Y+ add to give the more stable carbocation? As in the similar case of electrophilicaromatic substitution we invoke the Hammond postulate say that the lower energy carbocation ispreceded by the lower energy transition state. 13. Stereochemical OrientationIn addition to an unsymmetrical cyclic alkene, the two groups can come in from the more- or from theless-hindered face of the double bond.The rule is that syn addition is usually, although not always, from the less-hindered face.For example, epoxidation of 4-methylcyclopentene gave 76% addition from the less-hindered and 24%from the more-hindered face 14. ReactionsAddition of HCLMechanism 15. The slow or rate determining step is the protonation ofthe alkene to form a carbocation. The reaction will takethe lowest energy course at this stage. The most stablecarbocation will form by rearrangment. This determinesthe regioselectivity of the reaction. 16. Rearrangement via hydride shift or methylHydrideshiftMethyl shift 17. Rearrangement to form stable carbocations 18. Addition according to markovnikovs rule 19. Addition of HBr by free radical mechanism Antimarkovnikoves ruleWhen peroxides are added, the addition of HBr occurs by a free radical mechanismand the orientation is anti-MarkovnikovFree-radical addition of HF and HI has never been observed., even in the presence ofperoxidesFree-radical addition of HF, HI, and HCl is energetically unfavorableIt has often been found that anti-Markovnikov addition of HBr takes place even whenperoxides have not been added. This happens because the substrate alkenes absorboxygen from the air, forming small amounts of peroxides 20. Adding water (H OH) across the double bondThe simplest way is to reflux water and alkene with acidcatalyst essentially the same as H-Cl etc. It is a difficultreaction requiring quite forcing conditions. Mechanism 21. In presence of strong acid polymation product is obtained mechanism 22. Hydroborationmechanismanti-Marknikov 23. Addition of Br2- product form analogus to HBr additionMechanism- addition is anti 24. Not formed product 25. Addition to AlkynesThis is much more complex. The reason is that the cation is sp hybridized and ismuch less stablehydrogenation 26. Addition to carbonheteromultiple bonds 27. the addition reaction to the carbon hetro multiple bondsCarbon nitrogen bond1.2C=NCarbon oxygen bond.-C=OSince C=O, C=N, and CN bonds are strongly polar, with the carbon always thepositive end (except for isocyanides, ), 28. Addition tomechanismWho attack first ???????????Always nucleophile attack first ,in some cases electrophile may attackbut rate determining step is always addition of nucleophile.How they will attack???????????????If at beta position electron withdrawing group is present ------- synIf at beta position electron releasing grouup is present -----------anti 29. ReactivityBase ---- by donating its electrons to the nucleophile make it more powerfulnucleophile to attack on carbonAcid ---- increase positive charge on carbon increase its reactivity towardsthe nucleophileA &B electron donating ---------decrease activityA & B electron withdrawing------- increase activity.Conjugation ------------------------------increase activitySteric hinderence ------------------------------decrease activityAromatic aldehyde and ketones are more reactive than the aliphaticaldehyde and ketones. 30. Reactions Attack by hydroxyl groupThe Addition of Water to Aldehydes and Ketones: Formation of HydratesGemdiol(hydrateadduct) Mechanism (Acid)Stable only in water (Base) 31. Stability of hydrate+I ------------- decrease the stability--I -------------- increase the stabilityEg1 Hydrate of chloral are stable 32. Addition of water to carbon nitrogen double bondmechanismReagents used to cleave carbon nitrogen double bond1 Th(III) nitrate2 Aq TiCl33 CH3COOHW------OH (oximes)W-------NHCONH2(semicarbazone)W--------- NHAr(arylhydrazone)W--------Ar(shiffs base) 33. Hydrolysis of Aliphatic Nitro Compoundsreactionmechanism Hydroxamic acid intermediate 34. To increase the yield1Aq TiCl32 NaHSO33 activated dry silicagelIf concentration of sulphuric acid is increased fro 2M to 15.5M may changealdehyde back to hydroxamic acid 35. . Attack by OR or SR (Addition of ROH; RSH) mechanism 36. For acid------------ NaOH with 6-12% H2O2 is usedTO stop at amide--------- Conc H2So4, HCOOH with HCl or HBr,sodiumpercarbonate is used 37. reactionmechanism 38. reactionMechanism - it is not clearEgIsocyanic acidcarbamate 39. The addition of dry HCl to a mixture of a nitrile and an alcohol in theabsence of water leads to the hydrochloride salt of an imino ester(imino esters are also called imidates and imino ethers). This reaction iscalled the Pinner synthesis 40. Attack by ammonia derivatives on carbonyl compoundsMannich reaction:The Mannich reactio consists of an amino alkylation of anacidic proton placed next to a carbonyl functional group with formaldehydeand ammonia or any primary or secondary amine. The final product is a -amino-carbonyl compound also known as a Mannich base 41. mechanismStep1 ---formaldehyde + amine = amineStep2 ---ketone---- enole formStep3--- enol form--- cabanionStep 3--- imine form carbocationStep 4---- carbocation + carboanion= mannich base 42. Addiition of hydrazine derivativeFormation of :-1 hydrazone2 osazone3 pyrazolonehydrazone The product of condensation of a hydrazine and an aldehyde or ketone is called a hydrazone. 43. osazone-Hydroxy aldehydes and ketones and a-dicarbonyl compounds give osazones, inwhich two adjacent carbons have carbonnitrogen double bonds 44. Pyrazolonebeta keto esters gives pyrazolones 45. Attack by hydroxyl amineoximes can be prepared by the addition of hydroxylamine to aldehydes orketones.mechanism 46. ImportantMaximum rate at pH 4Step 1 is base catalysed at high pH hydroxylamine will be protonated andcan not attack to the carbonnyl carbonStep 2 is acid catalysedStep I is slow and rate determiningAt high pH rate determining step will be step2 47. Attack by halogenFormation of gem halideIn presence of alpha carbon vinylic chloride will be as side product orsoetimes main product 48. Attack by organo mettalic compoundsGrignard reactionOrganomagnesium compounds, commonly known as Grignard reagents(RMgX), are formed by the reaction of alkyl, vinyl, or aryl halides withmagnesiummetal, usually in ether solvents such as diethyl ether or THF Formaldehyde -------------primary alcohol Other aldehyde --------- sec alcohol Ketone --------- tertiary alcohol 49. Reformatsky reaction Alpha halo ester Beta hydroxy acidInermediateReactivity increasedby:-1 activated zinc2 zinc/silver graphite3 zinc and ultra sound 50. Carbon Attack by Active Hydrogen CompoundsAldol rectionsReactions are base-catalyzed condensations. base removes a CH proton to give acarbanion, which then adds to a CO. The oxygen acquires a proton, and the resultingalcohol may or may not be dehydrated, depending on whether an a hydrogen ispresent and on whether the new double bond would be in conjugation with doublebonds already present. Retrograde aldol reaction becauuse all the steps are reversible 51. Scope of aldol reactions1. Two same aldehyde with alpha H2. Two same krtone wiith alpha H3. Two different alldehyde one may not haver alpha H4. Two different ketone5. One aldehyde and one ketone.:-feasable if aldehyde has no alpha hydrogen ,if aldehyde also having alpha hydrogen only alpha carbon of the ketone will add to the carbonyl cabon of aldehyde 52. The Knoevenagel ReactionThe condensation of aldehydes or ketones, usually not containing an ahydrogen, with compounds Reaction 53. The Perkin Reaction The condensation of aromatic aldehydes with anhydrides is called the Perkin reactionBase is generally the salt of acid corresponding to the acid anhydride,.Alpha hydroxy never isolated always dehydrated to form - unsaturatedcompoundsWhen acid anhydride contains only one active methylene hydrogen thenhydroxy compounds can be isolated. 54. Tollens ReactionIn the Tollens reaction an aldehyde or ketone containing an hydrogen istreated with formaldehyde in the presence of Ca(OH)2 or a similar base.mechanism 55. If aldehyde and ketone having several hydrogen they all can bereplaced Pentaerythritol 56. Benzoin condensationWhen certain aldehydes are treated with cyanide ion, benzoins are producedin a reaction called the benzoin condensationreactionMechanism 57. Addition to carbon sulpherbondNucleophilic substitution at RSO2X is similar to attack at RCOXReaction 58. DescriptionSulfonyl chlorides as well as esters and amides of sulfonic acids can be hydrolyzed to the corresponding acids. Sulfonyl chlorides can by hydrolyzed with water or with an alcohol in the absence of acid or base Basic catalysis is also used but the salt is the product obtained.. Usually involves R-O cleavage, except when Ris aryl. 59. REFERENCESSmith B. Micheal & March Jerry; Marchs Advanced OrganicChemistry, Reaction, Mechanism and Structures; Wiley-Interscience John wiley&son inc, Publication, New Jersey; VI edition; 2007; 999-1476; 60. THANKYOU