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     rearrangement reaction rearrangement reaction Presentation Transcript

    • REARRANGEMENT REACTION Prepared by:Ashwini.M.Londhe (F. Y. Mpharm) Guided by:Dr.A.R.Chabukswar 1 MAEER”S Maharashtra institute of pharmacy.
    • CONTENT1) Pinacol rearrangement2) Bechmann rearrangement3) Heck reaction4) Ozonolysis5) Grignard reaction6) Use of diazomethane 2
    • PINACOL REARRANGEMENT Wilhelm Rudolph Fittig (6 December 1835 – 19 November 1910) was a German chemist. Fittig discovered the pinacol coupling reaction. R R R C C R OH OH Pinacol are ditertiary 1,2-diols. the simplest member of this class is Me2C(OH).C(OH)Me2. 3
    •  when pinacol is treated with dilute moderately conc. H2SO4 a rearrangement reaction takes place which leads to the formation of Me3C.CO.Me(pinacolone). O CH3 CH3 CH3 H CH3 C C CH3 CH3 C C CH3 OH OH CH3 Pinacol Pinacolone The acid catalysed rearrangement of vic diols (1-2 diols) to ketone or aldehyde with elimination of water is known as Pinacol pinacolone rearrangement. Example shows that the migration origin and migration terminus are the two adjacent carbon atoms. the migrating group may be aryl group, or alkyl an H atom. 4
    • Mechanisms:Step1: reversible protonation to a hydroxyl group and elimination of watermolecule R R R R R R H R C C R R C C R C C R OH OH OH2 R OH OHStep2: formation of non-classical carbenium ion ,a bridged intermediate. R R R C C R C C R R R OH R OH Bridged intermediate 5
    • Step3:actual migration of a group to form the classical carbenium ion. R R R R C C R C C R3C CR R OH OH O H R OHBridged intermediateStep4: The loss of proton and the formation of oxo compound. R R R3C C R3C + H C O H O 6
    • STEREOCHEMISTRY: Reaction is intra molecular. When different group are present on C atom bearing the hydroxyl groups ,two question arise. Ph Me 1. Which of the two OH group will 1. Which of the two OH group be protonated. will be Protonated? Ph C C Me 2. Which of the group will migrate? HO OH 2. Which of the group will migrate?2-methyl-1,1-diphenylpropane 7
    • Answer of Q1 Stability order of the carbenium ions. Decreasing stability order of carbenium ion isPh2CH > Ph CMe > PhCH >(CH3)2C .CH3CH Usually that OH receives the proton which produces the more stable carbenium ion by elimination of water molecule. thus in this example OH gr. On the C atom holding the phenyl gr Will receive the proton since the stability of diphenyl carbenium ion is greater than that OH dimethyl carbenium ion. Stability of carbenium ion depend on the delocalization of positive charge on the C atom either through resonance or through hyper conjugation. 8
    • Answer of Q2 There is no clear cut answer in so far as migratory preference is concern. It has found that a gr in anti or trance position with respect to the leaving group ,H2O, in the more stable conformation of the Protonated substrate migrate preferentially. Ph Me Me H2SO4 Ph C C Me Ph C C Me HO OH Ph O 2-methyl-1,1-diphenylpropane-1,2-diol 9
    • Do the reaction conditions (i.e. type of acid, concentration, solvent and temperature) influence the course of rearrangement? oThus the action Of cold ,concentrate H2SO4 on comp A produces mainly the ketone B while treatment of A with acetic acid containing traces H2SO4 of gives mostly C phenyl migration. cold CH3COOHMe Ph C CMe2 C CPh2 Ph2C CMe H2SO4 a trace of H2SO4 O Ph O Me OH OH ketone B compound C compound A oGenerally Aldehyde formation is favored by use of mild condition (lower temp,weker acid) oUnder more drastic condition aldehyde may be converted to ketone. 10
    • Application:1) synthesis of carbonyl compounds from alkenes. CH3 CH3 CH3 Cl2 moist CH3 C CH2 CH3 C CH2Cl CH3 C CH2OH Ag2O Cl OHl O CH3 CH3 C CH H Dimethyl acetaldehyde2) Ring expansion of cyclic ketone O HO CH3NO2 HO CH3NH2 N HO CNH EtONsa H NaNO2 HCl CH3NO2 -H -N2 O 11
    • 3) Ketones from cyclic diols. Pinacol rearrangement has been employed to produce ketone which are other wise very difficult to synthesize. O OH OH 1 Mg,ether H O 2 H2O cyclopentanone pinacol4) highly branched oxo comp are very difficult to produce by other reaction pinacol rearrangement has interesting application in synthesis. O H3O H(CH3)2C.Cl.CHCl.CH3 (CH3)2C.OH.CHOH.CH3 (CH3)2C.OH.C CH3 Heat 12
    • BEKMANN REARRANGEMENT The Beckmann rearrangement, named after the German chemist ERNST OTTO BECKMAN (1853–1923),It is It is an acid catalyzed conversion of keto oximes to N substituted amides usually called the Bechmann rearrangement. reaction R 1.PCL5/ether O C N or H2SO4 R C NHR R 2.H2O OH 13
    • OXIMESoIn organic chemistry, compounds containing the grouping C = N-OH, derivedfrom aldehyde and Ketones by condensing them with hydroxylamine.oTwo types of oximes are known:Aldoxime: combination of aldehyde with hydroxylamine.Ketoxime: Combination of Ketones with hydroxylamine. RCHO + RHC=NOH H + NH2OH R2CO R2C=NOH 14
    • MECHANISMStep1) Formation of a better leaving group R R OH2 OH H2SO4 C N C N R RStep2) Ionization stepmigration of anti group (w.r.t.leaving group) loss of leaving group RR OH2 OH2 C C R.D.step N N R C N RR R R C N R 15
    • Step3) Nucleophilic attach by water molecule to carbenium ion O H H OH2 H2OR C N R -H C N R C N R R R O R C NHR 16
    • STEREOCHEMISTRY Reaction is intramolecular.Me OH OH Me c N + 1. H2SO4 c N MeCONHPh + MeCONHMe 2. H2OPh Me In high polarity solvent rate of reaction is fast. Rate of reaction also increase as stability of leaving group(anion)increase. CH3COO-< ClCH2COO<PhSO3- 17
    • oIt is found that the migrating group is always anti(i.e. tras)to thehydroxy group.thus the reaction is steriospecific Me Me H2N C H2N C N N Cold OH NaOH O Br (1) (3) Me OHH2N C No reaction N NaOH Br (2)E.g.the rearrangement of the two isomeric oximes of 2-bromo-5-nitrophenyl isooxamines.OH and Me gr.in isomer (1)are close enough for reaction ,and 18anti(trans)to each other.
    •  Direct exchange of the leaving group and the migrating group do not occure between N and C atom. H218O Ph2CNOH PhCONHP + PhC 18ONHPh Bechmann rearrangemen Oxygen atom come from medium. 19
    • APPLICATION This reaction offers good method of preparing anilides. Me 1.H2SO4 c N PhCONHMe 2. H20 Ph OH Synthesis of isoquinoline OH H CH C N CH CH CH P2O5 -H2O N C cinnamaldehyde oxime H Isoquinoline 20
    • oConfigration of ketoxime can be assigned . Steps I. Conversion of oxime into n-substituted amides. II. Hydrolysis of N- substituded amide. III. Isolation and identification of the product. O Ph OH 1. PCl5/ether H3O C N Ph.CNH C6H4CH3(P) PhCOOH + 2. H2O P-CH3C6H4NH2 p-CH3C6H4 B-isomeranti-p-tolyl phenyl ketoxime o Ph 1. PCl5/ether H3O C O C6H4CH3(P) CNHPh PhNH2 2. H2OC6H4H3p- OH P-CH3C6H4COOH C A-iomer anti-phenyl-p-tolyl ketoxime 21
    •  Synthesis of nylone-6,textile polymer NH2OH 1. PCl5/ether O 2. H2O N OH O N OH heat base O NH(CH2)5.C NH C (CH2)5 O 22
    • HEAK REACTIONS oRichard Fred Heck (born August 15, 1931)is an American chemist. oHeck was jointly awarded the Nobel Prize. owith the Japanese chemists Ei-chi-negishi and akira suzuki for their work in palladium catalysed coupling reaction in organic synthesis. 23
    • Introduction: This is coupling reaction in which the R group in RPdX (X=halied or acetate)replace hydrogen at the less hindered carbon atom of an alkene. (R =aryl,alkenyl,alkyl group). The palladium(0) catalyst is then regenerated using a base in the reductive elimination stepCR2 CH2 + RPdX R2C CH R Preparation of reagent: ArPdI :treatment of an aryl iodide with palladium acetate in presence of base. RPdI :from iodine and P(OA)2 in presence of weak base such as Bu3N. 24
    • MECHANISM PdX RPdX syn addition RRPdX + R R R" R" R" R H Rotation H R" PdX Syn elimination H R R" R R R 25
    • STERIOCHEMISTRY: The reaction are steriospecific. CR2 CH4 + RPdX R2C CH R occur by syn-addition of RPdX followed by syn-elimination of HPdX.. there is inversion of configuration. ethylene is the most effective olefin. increasing substitution lowers the reactivity. thus substitution take place at the less highly substituted side of double bond. The rate of coupling is strongly dependent on steric effect: for e.g. in the reactivity sequence.. 26
    • APPLICATION:It has many applications in target oriented synthesis The Heck reaction has been used in more than 100 different syntheses of natural products and biologically active compounds The first example is for the synthesis of Taxol®, where the Heck reaction was employed for creating the eight-membered ring. In the other example an intramolecular Heck-type coupling provides the morphine skeleton and the product is transformed to morphine in a few steps OH SBD N OH H O Heak reaction Me N Morphin MeO I 27 OBn
    • OZONOLYSIS Ozonolysis is the cleavage of an alkene or alkyne with ozone to form organic compounds in which the multiple carbon– carbon bond has been replaced by a double bond to oxygen. O O Zn + HOAc C C CH CH C O C O + O3 O +Ozonolysis is the process by which ozone (O3) reacts with alkenes(olefins) to break the double bond and form two carbonyl groups.If the double bond of the alkenes is substituted with hydrogen orcarbon atoms, the carbonyl groups that are formed are either 28aldehyde or Ketones.
    • Preparation:Generally, ozone is generated from air or oxygen and passed througha cold solution (from 0 to -78 °C) of solvent and substrate until a bluecolor is observed, indicating destruction of the double bond. OZONE electric discharge O2 or O3 cosmic rays 29
    • OZONIDE AND MOLOZONIDE STRUCTURES molozonide ozonide forms initially forms after rearrangement 30
    • MECHANISM R O O R R R HO O R R H 2O O + R H H O OHR H RHO O R HO R + H2 O H OH O 31
    • STEREOCHEMISTRY: alkynes are less reactive than alkene Olefins in which the double bond is connected to electron donating group react many time faster than those in which it is connected to electron withdrawing group. Ozonolysis of triple bond is less common and the reaction proceeds less easily, since ozone is electrophilic agent. The benefits of ozonolysis: Ozone oxidation is very economical during organic synthesis because it only uses air and electricity to convert olefins to carbonyl compounds Ozone oxidation is a very green technology because the only by-product of the organic syntheses is oxygen. That means that there aren’t any metal waste-streams to dispose of afterward. 32
    • APPLICATIONS: The safe use of ozone as an oxidant in organic synthesis is becoming increasingly popular. Industrial-Scale Ozonolysis; It is used in preparation of a generic steroid on a multikilo scale. vitamin D analog. S)-Hydroxyvitamin D Oxandrolone is an anabolic steroid used to promote weight gain following extensive surgery, Ceftibuten and Cefaclor Ceftibuten is a third-generation oral cephalosporin, hasexcellent Gram-negative activity, and possesses a high degree of â- lactamase stability 33
    • GRIGNARD REACTION François Auguste Victor Grignard (May 6, 1871 in Cherbourg - December 13, 1935 in Lyon) was a Nobel Prize-winning French chemist.  Introduction  Formula RMgX.it is prepared by the reaction of metallic magnesium with the appropriate organic halide.(R=ALKYL/ARYL/ALKENYL) halied in order of reactivity (I> Br> Cl>> F).RX + Mg RMgX Anhydrous ether Grignard reagent 34
    •  Organolithium compound: Less prone to unwanted side reaction. Lithium is more electropositive than magnesium. Carbon lithium bond are more polar than carbon magnesium bond. This are more reactive than Grignard reagent. halide.(R=ALKYL/ARYL/ALKENYL) halide in order of reactivity (I> Br> Cl>> F). RX + 2Li Anhydrous ether RLi +LiX Grignard reagent WHY GRIGNARD SYNTHESIS IS SO IMPORTANT? because it unable us to take two organic molecules and convert them in to bigger one. 35
    • Reaction: C O + RMgX C OH + Mg(OH)X RMechanism: Alcohol 36
    • STEREOCHEMISTRY the reaction of carbonyl group can establish a steriocenter.if the reactant are symmetric ,equal amount of the two enantiomers are formed, O Me HO 1)MeMgI OH Me + 2)H Ph Et Ph Et Ph Et 1Parts 1 part•If one of the reactant are asymmetric, there is a predominance of theone of the two possible diastereomers H Me H Me H Me Mr Mr 1)MeMgI + Ph PhPh CHO 2)H HO H 37 H OH 2 PART 1 PART
    • REACTIONS: reactions are classified with reference to the type of compound which is obtained.  Hydrocarbons: XMg R + CH3 X R CH3 + MgX2Grignard reagent react with alkyl halides and related compounds in theSN2manner.the reaction with saturated halide are slow and the yields poor ,butallyl and benzyl halide(more reactive than alkyl halide)react Efficiently.oAlcohol: R R R H XMg R + O R O MgX R OH "R "R "RGrignard reagent react at the carbonyl carbon of aldehyde and ketone to givealcohols. 38
    •  Aldehyde:The reaction of Grignard reagent with ethyl orto format gives an acetal which is converted by mild acid hydrolysis into the aldehydeEtO EtO OEt + RMgX OEt + RMgOEt + XEtO EtO oKetones: Three methods are available 1)from nitriles. RRMgX + R C N O R 39
    •  2)from N-substituted amides. R R MgX + R"2NHRMgX + O O+ N2"R R 3)from acid chlorides C6H11 Ph 1)PhCOClC6H11MgBr 2)H O 40
    •  Reaction at element other than carbon:  Grignard reagent may be used to attach various other element to carbon. The following type of compound can be obtained. 1) hydro peroxide O2 O MgX HMe3C MgX Me3C O Mg3C CO2H 2) Thiols RMgX + S R S MgX 41
    • 3) sulfinic acids O OH HRMgX + SO2 R S MgX R S O O4)iodide. RMgX + I I R I + MgXI5)aminesRMgX + NH2 OCH3 R NH2 + MgX(OCH3) 42
    • Limitation: Solvent must be scrupulously dried and freed of the alcohol from which it was very probably made. Grignard reagent will not even form in the presence of water. Apparatus must be complelty dry before start. Protect reaction from reaction from water vapors. Grignard reagent can not prepare from a compound (HOCH2CH2Br) that contain addition halogen/some other group (-OH) that will react with a Grignard reagent. In preparation of aryl magnesium halide substituent present on benzene ring like –COOH.-OH,-NH2,-SO3H contain hydrogen attach to O or N are so acidic that they decompose Grignard reagent . 43
    •  Protecting group (THP) tetrahydropyranyl: Used to prevent unwanted reaction. The unsaturated cyclic ether 2,3- dihydro-4H-pyran (DHP)react with alcohol in presence of acid to give alkyl tetrahydropyranyl ether. THPether resistant to base and many other reagent It is easily attached and easily removed. 44
    • DIAZOMETHANE Introduction Frmula:CH2N2 USES: ethylating agent for acids,alcohols,amines,carbines,aldehydes. Physical properties: diazomethane is yellow gas.(b.p.-23°c).it is highly toxic and explosive. It explodes even iv gaseous state. It decompose redially. Storage condition: its ethereal solution may be stoared at 0°c for about 24 hrs without appreciable decomposition. Diazomethane is a resonance hybrid of the following canonical structures.CH2 N NH CH3 N N CH2+ N N- 45
    • Various N-nitoso-N-alkyl amidesundergo elimination with a base to givediazomethane. The most use full andconvenient general method foe thepreparation of diazomethane is thetreatment of N-nitoso-N-methyl amidewith alkali in ether 46
    •  Reaction: O Ether R C N NO + NaOH CH2N2 + H2O + RCOONa CH3 Mechanism; N O N C CH3 CH3 N N O C CH3 O ON-methyl-N-nitrosoacetamide Methanediazoaetate H2 + H C N N OCOCH3 CH2 N N + H2O + CH3COONa 47 Diazomethane
    • several N-nitoso-N-methyl compound have been used to prepare diazomethane.  1.from (N-nitoso-N-alkyl) terephtalimide. NO NO 2NaOHCH3 N C C N CH3 2CH2N2 + COONa COONa O O  2. from (N-nitoso-N-alkyl)-p-toluenesulphonamide. CH3 Ethanlic SO2 N CH3 CH3 SO2OK + KOH NO CH2N2  3.from (N-nitoso-N-alkyl)-N’-nitroguanidine with pottassium hydroxide. NH KOH CH3 N C NHNO2 CH2N2 Warm 48 NO
    • Safety:oDiazomethane is toxic by inhalation or by contact with theskin or eyes (TLV 0.2ppm). Symptoms include chestdiscomfort, headache, weakness and, in severe cases,collapse.oLike any other alkylating agent it is expected to becarcinogenic, but such concerns are overshadowed by itsserious acute toxicity.oCH2N2 may explode in contact with sharp edges, such asground-glass joints, even scratches in glassware.oGlassware should be inspected before useThe compound explodes when heated beyond 100 °C. 49
    •  Advantages: Used as a methylating agent for reasonably acidic compounds. It provides method for the conversion of acids into their higher homolog. it react rapidly even without catalyse.and the yield is high. The reaction is clean since other product is nitrogen. It is the most use full and versatile reagent foe preparative purpose. Process: The reaction is carried out at about 0°c by adding ethereal solution of diazomethane to the solution of the substrate in ether till evolution of nitrogen ceases and yellow colour persist. 50
    • Application: METHYLATION Carboxylic acids: it is methylating agent for acidic compound such as carboxylic and mineral acids. Carboxylic acids can be converted to esters .reactivity of reagent increases with acidity. Reaction is used where the acid is sensitive to higher temperature. CH2N2 CH2N2 RCOOH -N RCOOCH3 C6HOH C6H5OCH3 -N2 2 CH2N2 CH2 COOH CH2COOCH3 methyl 2-cyclopropylacetate 51 2-cyclopropylacetic acid
    •  Alcohols:1) it produce a methyl ethers.2) Alcohols do not react at all unless a catalyst such as HBF3 or silica gel is present.3) Hydroxyl compound react better as their acidity increases.4) it is used chiefly to methylate alcohol and phenol that are expensive are available in small amount ,since the conditions are mild and high yield are obtained. 52
    • CH2N2 R OH + BF3 R O BH3 R O CH3 + BF3 + N2 H HBF4CH3(CH2)CH2OH + CH2N2 CH3(CH2)6CH2OCH3 + N2 propan-1-ol 1-methoxyoctane 53
    •  carbenes: the reaction is non selective.carbene react with hydrocarbon by insertion into carbon-hydrogen bond. not used in synthesis. C H + CH2 C CH2 H CH2N2 + UV n-hexane N-PENTANE + 2-methyl pentane 3-methyl pentane (E) + CH2N2 54 2-BUTENE 1,2-dimethyl cyclopropane
    •  Amines:primary aliphatic amines gives mixture of primary,secondary,and tertiary amines are obtained. The acidity of amines is less so catalyst like BF3. BF3 CR2N2 + R2NH CHR2NR2 Aldehyde and ketone:Converted in to the next higher analogue. N N R R O CH2N2 -N2 R R RR O R 55
    •  Acid chloride: It gives diazo ketone. If diazo ketone is heated in presence of silver oxide, under go wolff rearrangement to give ketene. When this is carried out in presence of water or alcohol, the ketene is directly converted into acid or ester. R Cl R R -H CH2N2 N N N N O O O R R C C O -N2 N N H O R R COOH C C O + H2O 56 H
    • REFERANCE1) Kalsi p.s..organic reaction and their mechanism.2nd edition, new age international publishers.509,634,635.2) Stuart warren. Organic synthesis, the disconnection approch.wily student edition.52,262,201,252,299.3) Jerry march a.wiley.advance organic chemistry ,reaction mechanism, and structure,4th edition a wiley interscience publication.1072-1097.4) Francis a. carey,richard j. sunberg.advanced organic chemistry, a reaction and synthesis. Part B.5th edition.springer publication.p.no.883-889,1091,715-723.5) S.n.sanyal.reaction rearrangement and reagent.bharathi bhawan publication and distrubutors.206-210,158-1596) Sachin kr ghosh.organic chemistry a modern approch.2nd.books and allied (p) ltd.702-706,715-710. 57
    • 58