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Lecture 1 c c bond formation
- 1. D R . V. S I VAM U R U G A N P R O F E S S O R I N C H E M I S T RY PAC H A I YA P PA’ S C O L L E G E , C H E N N AI – 6 0 0 0 3 0 S I VAAT N U S @ G M A I L . C O M FORMATION C-C BOND 29-12-2018 1
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- 4. 1.1 Main-group chemistry 1.1.1 Alkylation of enolates and enamines 1.1.2 Conjugate addition reactions of enolates and enamines 1.1.3 The aldol reaction 1.1.4 Asymmetric methodology with enolates and enamines 1.1.5 Organolithium reagents 1.1.6 Organomagnesium reagents 1.1.7 Organozinc reagents 1.1.8 Allylic organometallics of boron, silicon and tin 1.2 Transition-metal chemistry 1.2.1 Organocopper reagents 1.2.2 Organochromium chemistry 1.2.3 Organocobalt chemistry 1.2.4 Organopalladium chemistry 29-12-2018 4
- 5. 1.1.1 ALKYLATION OF ENOLATES AND ENAMINES Carbonyl groups increase the acidity of the proton(s) adjacent (α-) to the carbonyl group. The acidity of the C-H bonds in these compounds is caused by a combination of the inductive electron- withdrawing effect of the unsaturated groups and the resonance stabilization of the anion formed by removal of a proton Order of electron withdrawing capacity: NO2>COR>SO2R>CO2R>CN>C6H5 29-12-2018 5
- 7. • It is these enolate anions that are involved in many reactions of carbonyl compounds, such as the aldol condensation, and in bimolecular nucleophilic displacements 29-12-2018 7
- 8. TABLE 1.1. APPROXIMATE ACIDITIES OF SOME ACTIVATED COMPOUNDS AND COMMON REAGENTS 29-12-2018 8
- 9. • In the presence of a protic acid, ketones may be converted largely into the enol form, implicated in many acid-catalysed reactions of carbonyl compounds. 29-12-2018 9
- 10. ALKYLATION ON ENOLATE • Alkylation of enolate anions is achieved readily with alkyl halides or other alkylating agents. • Both primary and secondary alkyl, allyl or benzyl halides may be used successfully • tertiary halides poor yields of alkylated product often result because of competing elimination. • Advantageous - proceed by way of the toluene-p-sulfonate, methanesulfonate or trifluoromethanesulfonate rather than a halide. • The sulfonates are excellent alkylating agents and can usually be obtained from the alcohol in a pure condition more readily than corresponding halides 29-12-2018 10
- 11. With secondary and tertiary allylic halides or sulfonates, reaction of an enolate anion may give mixtures of products formed by competing attack at the α- andγ- positions Dialkylation also becomes a more serious problem with the more acidic cyanoacetic esters and in alkylations with very reactive electrophiles such as allyl or benzyl halides or sulfonates 29-12-2018 11
- 12. REACTION WITH ARYL/ALKENYL COMPOUNDS Benzyne Reactive intermediate 29-12-2018 12
- 13. INTERMOLECULAR ALKYLATION OF AN ESTER 29-12-2018 13
- 14. 29-12-2018 14
- 16. 2 AND 9-ALKYLATED TRANS- DECALONE 29-12-2018 16
- 18. 1.1.2 CONJUGATE ADDITION REACTIONS OF ENOLATES AND ENAMINES Addition to α,β-unsaturated carbonyl or nitrile compounds to the enolates – Micheal addition 29-12-2018 18
- 19. ADDITION OF PHENYL VINYL SULFOXIDE • The electron-withdrawing group is commonly an ester or ketone, but can be an amide, nitrile, nitro, sulfone, sulfoxide, phosphonate or other suitable group capable of stabilizing the intermediate anion. 29-12-2018 19
- 22. REACTION WITH ENDOCYCLIC ENAMINES 29-12-2018 22
- 24. SILYL ENOL ETHERS STABILISED ENOLATES 29-12-2018 24
- 27. 29-12-2018 27
- 29. 1.1.3 THE ALDOL REACTION 29-12-2018 29
- 30. REACTION WITH METAL ENOLATES 29-12-2018 30
- 31. REACTION WITH BORON ENOLATES 29-12-2018 31
- 32. CLAISEN CONDENSATION - SELF- CONDENSATION PRODUCT 29-12-2018 32
- 33. 29-12-2018 33
- 34. STEREOSELECTIVE ALDOL REACTIONS • the syn or the anti (traditionally erythro and threo) aldol product can be prepared. This is often termed a diastereoselective reaction • suitable chiral auxiliaries or catalysts, high selectivities for one enantiomer of the syn or the anti diastereomer can be obtained -enantioselective reactions 29-12-2018 34
- 35. REACTION WITH CIS AND TRANS ENOLATE 29-12-2018 35
- 36. ZIMMERMAN–TRAXLER MODEL chair-like six membered cyclic transition state in which the ligated metal atom is bonded to the oxygen atoms of the aldehyde and the enolate 29-12-2018 36
- 39. PROSTAGLANDIN F2 BY COREYα 29-12-2018 39
- 40. CONVERSION OF ACID TO KETONE 29-12-2018 40
- 41. 29-12-2018 41
- 42. SIMMONS–SMITH-TYPE Reaction of dimethylsulfoxonium methylide with the enone 29-12-2018 42
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- 45. 1.1.6 ORGANOMAGNESIUM REAGENTS • Organomagnesium reagents are commonly referred to as Grignard reagents. • Typically, a Grignard reagent is formed by reaction of an alkyl halide (RX) in ethereal solvent with magnesium to give the species RMgX. • The ethereal solvent co-ordinates to the magnesium atom and the Grignard reagents are in equilibrium with the dialkylmagnesium species R2Mg and MgX2 (Schlenk equilibrium). 29-12-2018 45
- 46. REACTION WITH GRIGNARD REAGENT 29-12-2018 46
- 47. ASYMMETRIC GRIGNARD REAGENTS • Asymmetric induction occurs in the addition of a Grignard reagent to an aldehyde or ketone bearing a chiral auxiliary. • An example is the use of the 8-phenylmenthol ester 138, in which Grignard addition to the aldehyde occurs from the front face opposite the bulky substituent on the auxiliary and with the conformation of the carbonyl groups cis to one another 29-12-2018 47
- 49. CONJUGATE REACTION WITH IMIDE 29-12-2018 49
- 50. 1.1.7 ORGANOZINC REAGENTS Organozinc compounds are less nucleophilic and less basic than the corresponding organolithium or organomagnesium reagents. They can therefore effect chemoselective carbon–carbon bond formation in the presence of otherwise reactive functional groups. The most common method for the formation of an organozinc reagent involves the insertion of zinc metal into the carbon– iodine bond of an alkyl iodide. 29-12-2018 50
- 51. REFORMATSKY REACTION • Reformatsky reaction, in which an organozinc species is generated from an α- bromoester. 29-12-2018 51
- 52. CYCLISATION TO LACTONE Insertion of zinc into allyl bromides occurs readily, for example to give the allyl zinc reagent 145. Addition to an aldehyde occurs by attack through the γ-carbon atom to give a homoallylic alcohol. With substrate 145, bearing a β–ester group, the product homoallylic alcohol cyclizes spontaneously to give the lactone 146. 29-12-2018 52
- 53. In the presence of a Lewis acid, alkyl zinc halides react with aromatic aldehydes to give secondary alcohols. However, alkyl zinc reagents are less reactive than their allyl derivatives and reaction with aliphatic aldehydes is very sluggish.29-12-2018 53
- 55. REACTION WITH DIETHYL ZINC 29-12-2018 55
- 56. 1.1.8 ALLYLIC ORGANOMETALLICS OF BORON, SILICON AND TIN A useful reaction in organic synthesis is the addition of an allylic organometallic reagent to a carbonyl group. A number of different metals can be employed, although those of boron, silicon and tin have found the most use. The carbon–carbon bond-forming step is often stereoselective and generates the versatile homoallylic alcohol unit Oxidative cleavage of the product alkene to the aldehyde (or other carbonyl derivative) provides the -hydroxy-carbonyl compound and offers an alternative stereoselective approach to the aldol-type product. 29-12-2018 56
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- 61. 1.2 TRANSITION-METAL CHEMISTRY The use of transition metals to promote the formation of carbon–carbon bonds has grown tremendously in recent years. This section describes some of the important transformations using the metals copper, chromium, cobalt and palladium. 29-12-2018 61
- 62. 1.2.1 ORGANOCOPPER REAGENTS • There are various types of stoichiometric organocopper reagent, the most common being R2CuLi, RCu(CN)Li or R2Cu(CN)Li2. • For example, a lithium dialkylcuprate species, R2CuLi, often referred to as a Gilman reagent, is most conveniently prepared by reaction of two equivalents of an organolithium compound with copper(I) iodide in diethyl ether 29-12-2018 62
- 63. REACTION WITH GILMAN REAGENTS 29-12-2018 63
- 64. SYNTHESIS OF CIS-DECALONE, 168 29-12-2018 64
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- 67. THE E-ALKENE IS FORMED FROM THE E-ALKENYL HALIDE. LIKEWISE, THE Z-ALKENE IS FORMED SELECTIVELY FROM THE Z-ALKENYL HALIDE. 29-12-2018 67
- 68. 1.2.2 ORGANOCHROMIUM CHEMISTRY • Arylchromium complexes can be prepared easily, simply by heating the arene with chromium hexacarbonyl, Cr(CO)6 or by ligand exchange with (naphthalene)chromium tricarbonyl complex. • The desired arylchromium complex is generated, bearing the arene (η6 species) and three carbon monoxide ligands on the chromium(0) atom (18 electron complex) 29-12-2018 68
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- 70. REACTION WITH ORGANO CHROMIUM 29-12-2018 70
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- 72. 29-12-2018 72
- 73. 1.2.3 ORGANOCOBALT CHEMISTRY • The most common use of cobalt in organic synthesis is as its alkyne complex. • Addition of dicobalt octacarbonyl [Co2(CO)8] to an alkyne generates the stable organocobalt complex 184 that exists as a tetrahedral cluster 29-12-2018 73
- 74. PAUSON–KHAND REACTION • The reaction combines the alkyne, alkene and carbon monoxide, in what is formally a [2+2+1] cyclo addition 29-12-2018 74
- 76. 1.2.4 ORGANOPALLADIUM CHEMISTRY Organopalladium species tolerate many different functional groups and promote a variety of carbon–carbon (and other) bond-forming reactions with extremely high chemo- and regioselectivity. Oxidative addition of palladium(0) species into unsaturated halides or triflates provides a popular method for the formation of the -bound organopalladium(II)species. Organopalladium species generated by oxidative addition react with organometallic species or with compounds containing a π-bond, such as alkynes or alkenes. 29-12-2018 76
- 77. It is important to use an unsaturated (e.g. aryl or alkenyl) halide or triflate, as β-hydride elimination of alkyl palladium species can take place readily. Oxidative addition of palladium(0) into alkenyl halides (or triflates) occurs stereospecifically with retention of configuration. The palladium is typically derived from tetrakis(triphenylphosphine)palladium(0), [Pd(PPh3)4], or tris(dibenzylideneacetone) dipalladium(0), [Pd2(dba)3], or by in situ reduction of a palladium(II) species such as [Pd(OAc)2] or [Pd(PPh3)2Cl2]. 29-12-2018 77
- 78. STILLE REACTION – ORGANO STANNANE 29-12-2018 78
- 81. INSERTION OF CO 29-12-2018 81
- 82. SUZUKI REACTION – ORGANO BORON REAGENT 29-12-2018 82
- 83. INTERMEDIATE OF PROSTAGLANDIN E1 29-12-2018 83
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- 85. SONOGASHIRA CROSS-COUPLING REACTIONS Crosscouplings of two alkynes (Glaser reaction) provides diynes. 29-12-2018 85
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