Module-3_Lectures-2-5.pptx organic chemistry

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1. Module-3, Lecture-2

2. H—OH C C + OH C C H Acid-Catalyzed Hydration of Alkenes acid catalyzed hydration reaction in 50% H 2 SO 4 -50% H 2 O

3. (90%) 50% H 2 SO 4 50% H 2 O H 3 C H 3 C CH 3 H C C OH C CH 2 CH 3 CH 3 CH 3 Follows Markovnikov's Rule

4. Step (1) Protonation of double bond slow + H 3 C H 3 C C CH 2 O + H H H : + H 3 C H 3 C C CH 3 H + O H : :

5. Step (2) Capture of carbocation by water fast + H 3 C H 3 C C CH 3 H + O H : : + H O H : C CH 3 CH 3 CH 3

6. Step (3) Deprotonation of oxonium ion fast + H O H : C CH 3 CH 3 CH 3 O H : : H O + H H H : + + H O : C CH 3 CH 3 CH 3 ..

7. + H 2 O H + H 3 C H 3 C C CH 2 OH C CH 3 CH 3 CH 3 Principle of microscopic reversibility In an equilibrium process, the same intermediates and transition states are encountered in the forward direction and the reverse, but in the opposite order

8. + H—BH 2 C C H BH 2 C C Hydroboration reaction Hydroboration can be viewed as the addition of borane (BH 3 ) to the double bond

9. + H—BH 2 C C H BH 2 C C Hydroboration Step Hydroboration reagents: H 2 B H H BH 2 Diborane (B 2 H 6 ) normally used in an ether-like solvent called " diglyme ( bis (2-methoxyethyl) ether)" 1. Borane-tetrahydrofuran complex (H 3 B-THF) 2.

10. 10 Addition of borane (BH 3 ) or alkyl boranes to alkenes (or alkynes) is called hydroboration. Borane exists as a dimer, but solutions containing an electron donor, such as an ether, amine or sulfide, allow adduct formation. The complexes BH 3 ·THF and the borane–dimethyl sulfide (BH 3 ·SMe 2 ) are commercially available and provide a convenient source of borane. BH 3 ·SMe 2 complex is more stable than BH 3 ·THF and has the additional advantage that it is soluble in a variety of organic solvents, such as diethyl ether and hexane.

11. 11 The most important synthetic application of borane is for the preparation of alkyl boranes by addition to alkenes, a process known as hydroboration. In nearly all cases the addition proceeds rapidly at room temperature, and only the most hindered alkenes do not react. Hydroboration occurs by a concerted process and takes place through a four membered cyclic transition state. 4-Membered cyclic TS The reaction is stereospecific, with syn addition of the boron and hydrogen atoms. The reaction can also be stereoselective , with hydroboration taking place preferentially on the less hindered side of the double bond.

12. H 2 O 2 , NaOH H BH 2 C C H OH C C Oxidation Step Organoborane formed in the hydroboration step can be oxidized into alcohol by hydrogen peroxide

13. 13 Hydroboration-Oxidation of Alkenes: Anti - Markovnikov addition of H-OH/ syn addition of H-OH

14. Mechanism of Hydroboration syn addition of the H 2 B – H bond to the same face of the  -bond in an anti- Markovnikov sense

15. 15 Hydroboration of mono- and disubstituted alkenes with borane gives rise typically to a trialkylborane product. However, trisubstituted alkenes normally give a dialkylborane and tetrasubstituted alkenes form only the monoalkylboranes . The extent of hydroboration may also be controlled by the stoichiometry of alkene and borane. Disiamylborane (di- s - isoamyl group, dialkylborane ) 2-Methyl-2-butene ( Trisubstituted alkene) Thexylborane ( t -hexyl group, monoalkylborane ) 2,3-Dimethyl-2-butene ( Tetrasubstituted alkene)

16. 9-BBN (9-Borabicyclo[3.3.1] nonane ) 1,5-Cyclooctadien Disiamylborane , Thexylborane and 9-BBN (partially alkylated boranes) may themselves be used to hydroborate less-hindered alkenes. Addition of borane to an unsymmetrical alkene could, of course, give rise to two different products by addition of boron at either end of the double bond. Typically, the less-hindered end of the alkene double bond is also the more electron rich and therefore interacts better with the electron-deficient boron atom. However, the selectivity is diminished with increasing electronegativity of the substituent.

17. Reactivity with Borane With 1,2-disubstituted alkenes, however, there is little discrimination in reactions with borane itself. In addition, the region-selectivity in the hydroboration of terminal alkenes, although high, is not complete.

18. 18 Further, there is little difference in the rate of reaction of borane with differently substituted double bonds, so that it is rarely possible to achieve selective hydroboration of one double bond in the presence of others. These difficulties can be overcome by hydroboration with substituted boranes such as disiamylborane , thexylborane or 9-BBN . These reagents are less reactive and more selective than borane . For example,

19. 19 Important: Terminal alkenes react more rapidly than internal alkenes. Z-alkenes react more rapidly than E-alkenes.

20. 20 Thexylborane has been used to make trialkylboranes containing three different alkyl groups by stepwise addition to two different alkenes. Hydroboration of dienes with borane itself usually leads to the formation of polymers. The monoalkylborane , thexylborane can promote the hydroboration of dienes to give cyclic or bicyclic organoboranes . Less reactive alkene – Otherwise two alkenes can attacks at the same time 1,5-Hexadiene ( Thexylborane ) Boracycloheptane For example,

21. Module-3 , Lecture-3

22. Generally, Mechanism of hydroboration:

23. Mechanism of Oxidation:

24. 24 Some example: In the presence of Acetic acid

25. 25 Reactive isolation is tedious syn addition Symmetrical alkyne

26. 26 PCC ( Pyridinium chlorochromate )

27. 27 Alkenes react with water in the presence of strongly acidic medium to form an alcohol. Hydration of an alkene is reverse of the dehydration of an alcohol. For dehydration of alcohols, a concentrated dehydrating acid such as H 2 SO 4 or H 3 PO 4 is used to drive the equilibrium to favor the alkene. Hydration of an alkene on the other hand is accomplished by adding excess water to drive the equilibrium towards the alcohol. Hydration of Alkenes / Addition of Water

28. 28 Mechanism: Acid catalysed hydration of alkenes The mechanism is similar as addition of hydrogen halide. Hydration is regioselective ; it follows Markovnikov rule giving a product in which the new hydrogen has added to the less substituted end of the double bond.

29. 29 Some Examples:

30. 31 Many alkenes do not easily undergo hydration in aqueous acid. Some alkenes are nearly insoluble in aqueous acid, and other undergo side reactions such as rearrangement, polymerization or charing under strongly acidic conditions. In some cases, the overall equilibrium favors the formation of alkenes rather than alcohol. No amount of catalysis can cause a reaction if the energetics are unfavorable. Oxymercuration – Demercuration is another method for converting alkenes to alcohols with Markovnikov’s orientation . This method works with many alkenes, that do not easily undergo direct hydration, and it take place under mild reaction conditions. No free carbocation is formed , so there is no opportunities for rearrangement and polymerization. Hydration of Alkenes by Oxymercuration - Demercuration

31. General reaction: Mechanism:

32. Some Examples:

33. 34 Advantageous: This method is most commonly used in the laboratory. This method gives better yields than the direct acid catalyzed reactions. It avoids the possibility of rearrangement and it does not involve harsh reaction conditions. Disadvantageous: Organomercurial compounds are highly toxic, they must be used with great care and must be disposed properly.

34. 35 Conversion of alkenes to ethers. When mercuration takes place in an alcohol solvent, the alcohol serve as a nucleophile to attack the mercurinium ion. The resulting product containing an alkoxy group. Mechanism: Alkoxymercuration - Demercuration

35. 36 Solvent attacks on the mercurinium ion at the more substituted end of the double bond (where there is a more positive charge), giving Markovnikov’s orientation product. Some Examples:

36. Epoxidation of Alkenes (IUPAC name: Oxiranes ) Epoxidation: Conversion of olefin into oxiranes using oxidizing agents is called epoxidation. Nomenclature: Alkane / Cycloalkane

37. Types of Reagents: Per acids / Peroxy acids Hydrogen peroxide / OH - Alkyl hydroperoxides / Metal complexes Dioxiranes Hypohalo acids (HOX) Iodine catalysed epoxidations

38. a. Per acids / Peroxy acids (RCO 3 H) Preparation: Due to the easy liberation of nascent oxygen, peroxides used for epoxidation of olefins.

39. Use of m -CPBA: m -CPBA is used widely used in the laboratory Stable Low cost Easily soluble in most of the organic solvents. Solvents: Halogenated solvents: DCM, Chloroform Aromatic hydrocarbons: Benzene, toluene and Xylene Ethers: Diethyl ether and THF Alcohols: Methanol and Ethanol Acid: Acetic acid Water Temperature: ─ 10 o C to Room temperature

40. General Reaction: Mechanism: Transition state

41. Groups that are trans on the alkene will end up trans on the epoxide product. Groups that are cis on the alkene will end up cis on the epoxide product. Stereochemistry of the epoxidation: Syn addition of oxygen

42. Module-3, Lecture-4

43. Reactivity of olefins in epoxidation: Electron rich olefins are good nucleophiles, thus faster in epoxidation. Steric crowding can be neglected. Reactivity order:

44. Reactivity with respective to per acid: At carbonyl of per acid presence of electron withdrawing group increases the reactivity Trifluro peracetic acid (TFPAA) – Highly reactive per acid in epoxidation due to the presence of strong electron withdrawing group at carbonyl. Although TFPAA less commonly used in laboratory due to: Highly expensive Highly unstable (difficult to store) By-product, trifluro acetic acid opens the epoxide. To prevent the opening of epoxide, basic buffer or simple bases can be used in combination with TFPAA. Regioselectivity in epoxidations with peracids : If the compound contain multiple double bonds, selective epoxidation takes place at highly alkylated double bond. In a chemical reaction, if structural isomers produced in unequal ratio is regioselective .

45. Examples:

46. Stereoselectivity in epoxidation: In a chemical reaction, if stereoisomers produced in unequal amount is called stereoselective reactions. In epoxidations, stereoselectivity controlled by Steric crowding near the double bond and Chelation or H-bonding. At olefin if no steric crowding at top and bottom faces, epoxidation is equally probable in both faces, resulting product is in equal amount / equal ratio. Thus, no stereoselectivity in epoxidation.

47. ii. Near to unsaturation if there is a alkyl substituent, at double bond one of the face suffers from steric crowding at the time of epoxidation approaching reagent preferably deliver oxygen at sterically less crowded face. In the resulting product stereoisomers are in unequal ration, thus stereoselective epoxidation. Examples:

48. Chelation / H-bonding: At allylic position, if there is a chelating group (OH, NH 2 ) epoxidation preferably takes place at the same side of chelating group. Steric crowing supressed by chelation between group at allylic position and approaching reagent. Group at allylic position develops hydrogen bonding with reagent and holds specially at one face of olefin of unsaturation. Cyclic systems are best examples for chelating effect.

49. Examples:

50. 2. In some of the α , β unsaturated olefins, Baeyer- Villiger oxidation is side reaction or competitive reaction. 3. Peracids also in efficient in epoxidation of terminal alkenes because of low nucleophilicity . Limitations: 1. Peracids are inefficient in epoxidation of conjugated olefins

51. Epoxidation : diastereoselectivity

52. Ethylene H 2 C=CH 2 1 Propene CH 3 CH=CH 2 22 2-methylpropene (CH 3 ) 2 C=CH 2 484 2-methyl-2-butene (CH 3 ) 2 C=CHCH 3 6526 Relative Rates of Epoxidation

53. Examples:

54. b. Hydrogen peroxide / OH - H 2 O 2 /OH - is a alternative to peracids . It is mainly useful for the oxidation of conjugated olefins such as e.g. α , β -unsaturated carbonyl compounds, α , β -unsaturated nitriles and α , β -unsaturated nitro compounds.

55. Mechanism: Examples:

56. Module-3, Lecture-5

57. Oxidation of alkenes into 1,2-diols Opening of epoxides in acidic/basic medium (H + /OH - ) Prevost and Woodward hydroxylation ( RCOOAg /I 2 ) Osmium tetroxide (OSO 4 ) Potassium permanganate (KMnO 4 )

58. Opening of epoxides in acidic/basic medium (H + /OH - )

59. Mechanism: In acidic medium:

60. Alkenes → Epoxides → Anti 1,2-diol (Anti glycols) In basic medium:

61. b( i ). Prevost Hydroxylation (Dry hydroxylation/Anti hydroxylation) Alkenes → Anti 1,2-diol (Anti glycols). The reaction was discovered by the French chemist Charles Prévost .

62. Mechanism: Neighbouring group participation (NGP) 

63. b(ii). Woodward Hydroxylation (Wet hydroxylation/ Syn hydroxylation) Alkenes → Syn 1,2-diol ( Syn glycols). The reaction was discovered by American Organic Chemist Robert Burns Woodward .

64. Mechanism: Neighbouring group participation (NGP) 

65. Near to olefin if there is a substitution, Woodward hydroxylation preferably takes place at sterically more crowded side of the olefin.

66. In a molecule if there is a conjugated and isolated olefins. Woodwards hydroxylation takes place at isolated double bond.

67. c. Osmium tetroxide (OSO 4 ) – Syn hydroxylation OsO 4 is formed slowly when osmium powder reacts with O 2 at ambient temperature. Reaction of bulk solid requires heating to 400 °C. Alkenes → cis 1,2-diol. OsO 4 is expensive and highly toxic. Thus, it can be used in catalytic amount OsO 4 in the presence of co-oxidant Potassium chlorate (KClO 3 ) / hydrogen peroxide / N - methylmorpholine N -oxide (NMO) / K 3 Fe(CN) 6 in water can be used as a co-oxidant. Lewis bases such as tertiary amines and pyridines increase the rate of dihydroxylation. The ligand-acceleration arises via the formation of adduct OsO 4 L, which adds more rapidly to the alkene.

68. Mechanism: Osmate ester Cis addition VIII

69. Dihydroxylation : diastereoselectivity

70. Examples:

71. d. Potassium permanganate (KMnO 4 ) – Syn hydroxylation Cheaper solid Insoluble in organic solvents, but soluble in water. Limitations: Insoluble in organic solvents. Useful for organic compounds which are soluble in water. e.g. unsaturated carboxylic acid, unsaturated sulfonic acids and Oleic acid etc. Oxidation product depends on nature of reaction condition. In neutral and acidic medium over oxidation product produces. In basic medium usually products are 1,2-diols, over oxidation product almost negligible. Application: Alkenes → Syn 1,2-diol. Solvents: Water, aq. Benzene, aq. Acetone, aq. Alcohols, aq. Acetic acid, aq. Ether

72. Mechanism: Cold KMnO 4 /OH -

73. Similar to OsO 4 , selective hydroxylation takes place at sterically less crowded olefins in the presence of alkaline KMnO 4 . cis alkene + Syn addition → Meso compound trans alkene + Syn addition → Racemic mixture

74. If the reaction carried out using hot concentrated acidified potassium manganate (VII) solution;

75. Ozonolysis of Alkenes - + Oxidative cleavage of an alkene to carbonyl compounds (aldehydes and ketones). Both  - and  - bonds are breaking during the ozonolysis of alkenes. Unsaturated bonds of alkenes, alkynes and azo compounds are cleaved with ozone. Alkenes and alkynes multiple carbon–carbon bond has been replaced by a carbonyl group while azo compounds form nitrosamines. The outcome of the reaction depends on the type of multiple bond being oxidized and the work-up conditions. Useful for the determination of position of double bond in a molecule.

76. Mechanism: Mechanism proposed by  Rudolf Criegee (German organic chemist)  in 1953. Mechanism proceed through a Criegee intermediate or Criegee zwitterion. Carbonyl oxide ( Criegee zwitterion)

77. Mechanism: Oxidative workup

78. Mechanism: Oxidation of aldehyde to acids with H 2 O 2

79. Mechanism: Reductive workup

80. Overall reaction mechanism:

81. Examples:

82. Ozonolysis of alkynes: The exact mechanism is not completely known.

83. Examples:

84. Oxidative cleavage of alkenes

85. Oxidative cleavage: Ozonolysis