Metathesis Reactions. Dr. Mishu Singh Department of Chemistry M.P.Govt P.G.College, Hardoi

Transcription

1 Metathesis Reactions AB + CD AC + BD Dr. Mishu Singh Department of Chemistry M.P.Govt P.G.College, Hardoi 1

2 AgNO 3 + HCl AgCl + HNO 3 NaCN + NH 4 Cl NaCl + NH 4 CN 2

3 Metathesis Metathesis = Meta(Change) + thesis(position) It is the change of parts of two substances in a chemical reaction AB + CD AC + BD or AD + BC AgNO 3 + HCl AgCl + HNO 3 NaCN + NH 4 Cl NaCl + NH 4 CN 3

4 Metathesis in an organic reaction entails redistribution of alkenes/ alkynes fragments by the scission of carbon - carbon double/ triple bonds. Two and two bonds are broken and two new and two new bonds are formed. 4

5 Discovery of olefin Metathesis Olefin metathesis was first observed in the 1950s (Herbert S. Eleuterio, at Du Pont's petrochemicals department), The reaction was extended with cyclopentene polymer They tell "the polymer we got looked like somebody took a pair of scissors, opened up cyclopentene, and neatly sewed it up again" However real mechanism of these reaction remained the mystery till

6 Characteristics of Metathesis Reactions Olefin metathesis is an equilibrium process and with many alkenes, substrates yields a mixture of starting material and two or more alkenes products. However, with terminal alkenes, one metathesis product is ethylene gas (CH 2 =CH 2 ), which escapes from the reaction mixture and drives the equilibrium to the right. Thus, monosubstituted alkenes (RCH=CH 2 ) and 2,2- disubstituted alkenes (R 2 C=CH 2 ) are excellent metathesis substrates because high yields of a single alkene product. 6

7 Some Important Metathesis Reactions 1. Alkene Metathesis 2. Alkyne Metathesis 3. Enyne- Metathesis 7

8 Transalkylidination or Transalkylation? At first, it was questioned, whether, olefin metathesis is exchange of alkyl or alkylidene groups. Which one is correct? 8

9 Experimental proof for Transalkylidination 9

10 Fundamental Olefin Metathesis Reactions 10

11 1.Cross-metathesis: It is called as CM 11

12 2. Ring-closing metathesis Two double bonds must be in same compound. Ring formation ( cyclization ) occurs rapidly. 12

13 3. Ring-Opening Metathesis Polymerization C metathesis Ru C Ru metatheses n C n Ru 13

14 4. Acyclic Diene Metathesis polymerization + C 8 C 8 C Ru + C 14 C 2 Carrying this reaction out over and over with the more reactive terminal double bonds leads to acyclic diene metathesis (ADMET) polymerization with longer chain diene substrates. 14

15 The Catalysts Benzylidenebis(tricyclohexylphosphine) dichlororuthenium 2,6-Diisopropylphenylimidoneophylidene molybdenum(vi) bis(hexafluoro-t-butoxide) [1,3-bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene]dichloro(phenylmeth ylene)(tricyclohexylphosphine)ruthenium These are called carbene complex, metallocarbene or alkylidene complex 15

16 Schrock s catalyst Commercially available, as is synthetic precursor. Must be handled under argon or nitrogen using dry conditions. Relatively intolerant of proton on heteroatoms. Tolerant of S, P and nitrile functional groups. High reactive. Electron deficient Mo(VI), 14 electron species. N Ar ligand, OR ligand and initial alkylidine need to be bulky. Electron withdrawing alkoxides increase electrophilicity of metal center, hence increases reactivity. 16

17 Grubbs Catalyst Reasonably stable toward water, oxygen and minor impurities ease of handling. Lower activity vs. Mo and imido alkylidene catalyst. High functional group tolerance. Halides: catalyst activity I < Br < Cl. Ru catalyst containing N-heterocyclic imidazol-2- ylidene, Carbene. Activity is significantly higher then parent Ru complex. 17

18 The Nobel Prize In Chemistry 2005 For The Development Of Metathesis Method In Organic Synthesis 1. Dr. Yves Chauvin at the Institute Francisdupetrole, France 2. Prof. Robert H. Grubbs, California Institute of Technology USA 3. Prof. Richard R. Schrock, Massachusetts institute of Technology, Cambridge USA 18

19 2005 Nobel Prize for Metathesis 19

20 Explanation of the mechanism Wrong Turns 20

21 Chauvin s Mechanism 21

22 22

23 Alkynes Metathesis 23

24 Alkynes Metathesis Mechanism 24

25 Enyne metathesis The Enyne metathesis is a ruthenium-catalyzed bond reorganization reaction between alkynes and alkenes to produce 1, 3-dienes. Catalyst When the reaction is intramolecular, called as Ring Closure Enyne Metatesis RCEM Alkyledine migration from the alkene to alkyne carbon. The driving force thermodynamically stable 1,3-diene. 25

26 Mechanism Of Enyne Metathesis This is the proposed "yne-then-ene" mechanism.the driving force for the reaction is the formation of thermodynamically stable conjugated butadiene 26

27 Initiation : Enyne metathesis mechanism Catalytic Cycle : 27

28 Applications Metathesis in Chemistry Metathesis 28

29 Application Of Metathesis In Synthesis Of Biologically Active Compounds Highly functionalised novel bicyclic β-lactams synthesis These bicyclic β-lactams systems have been prepared via the enyne metathesis reaction using catalytic quantities of trans (Cy 3 P) 2 Cl 2 Ru=CHPh (Cy = Cyclohexyl) Chem. Comm.1997,

30 Complex Heterocyclic lactam Fused bicyclic lactams having quinolizidine alkaloid skeletons are commonly observed structural unit of many important compound which display a broad rang of biological activity. J. Org. Chem. 2004, 69,

31 Balanol It shows remarkable anticancer activity. Also used against HIV infection, Rheumatoid Arthritis, cardiovascular disorder, CNS dysfunction. 31

32 Formal Total Synthesis of Balanol A.Furstner, J. Org. Chem. 2000, 65,

33 Turrianes Turrianes are efficient DNA cleaving agents under oxidative condition in presence of copper ion and butyl amine. These are naturally occurring cyclophanes and consist of aromatic unit specially benzene and an aliphatic chain that form chain bridge between benzene ring. 33

34 Sphorolipid lactone They are natural products Sphorolipid derivatives have antibacterial and antifungal activity. Present study documents in vitro spermicidal and anti -HIV virucidal activities against human semen are similar to commercial spermicidal Nonoxynol-9 (N-9). 34

35 Partial Synthesis of Sphorolipid lactone Furstner, J.Org. Chem. 2000, 65,

36 Dehydrohomoancepsenolide Butenolide is natural product incampas a broad spectrum of antibacterial, antimalarial, antitumor and herbicidal activity. Dehydrohomoancepsenolide is a natural product. 36

37 Synthesis of Dehydrohomoancepsenolide Org. Lett. 2000, 2,

38 BILN BILN is a new chemical entity which shows promising results against the Hepatitis C virus by inhibiting Seine Protease of HCV. BILN developed by Boehringer-Ingelheim. BILN- 2061is in Phase II Clinical trial in US and Europe. BILN 2061, 15-membered macro cyclic compound containing a (Z)- olefin. 38

39 Synthesis of BILN-2061 Org. Lett., 2004,6,

40 Synthesis of ORL Pheromones The omnivorous leaf roler (OLR) is a pest of appels, pears, peaches, and nectarines. The OLR pheromone is an 82:18 ratio of E to Z-tetradecenyl acetate isomers. The C M metathesis reaction, using the second generation Grubbs`catalyst, produces the desired isomeric ratio. 40

41 MISCELLANEOUS Macrocyclisation Upto 30 membered ring can be synthesized Cis and trans isomers are formed Higher temperature generally required 41

42 Cyclo oligomerisation by Alkyn metathesis Synlett 2003,29 & Synthesis,2003,

43 CIVETONE It is one of the important valuable fragrance containing compounds used in perfume industry, chemically macrocyclic ketone. Stereoslective synthesis of Civetone Chem. comm. 2005,

44 Synthesis Of Phenanthrene Conversion of biphenyl to phenanthrene 44

45 Synthesis of Cyclophanes 45

46 Multicomponent, Tandem metathesis/diel s -Alder Cycloaddition Synthesis of heterocycle with multistereocenter Reaction Sequences Org.lett. 2003, 5,

47 Dendrimer a family of nano-sized, 3D polymer, a class of macromolecules having highly branched architecture The name comes from the Greek word δένδρον (dendron), which translates to "tree 47

48 Conclusions The examples mentioned above illustrate the broad applications of metathesis reactions for the synthesis of several drugs and many other valuable chemical compounds. Thus this reaction has great significance for both academic research and industry for development of commercially valuable compounds. The beauty of metathesis method is that it take shorter synthetic rout give higher yield, fewer by-products and it tolerates different functional groups, present in starting material. Thus metathesis chemistry has opened up novel opportunity to explore the enormous diversity of organic molecules and contribute to a green chemistry. 48

49 Drawing the Products of Alkene Metathesis 49

50 Exercises Give the major product of the following reactions 50