Module-3_Lectures-6-8.pptx physical chemistry

about oxidation and reduction

1. Module-3, Lecture-6 Oxidation of Alcohols to carbonyls

2. Oxidation: Addition of oxygen or removal of hydrogen in a chemical reaction. Chromium-based Reagents H 2 CrO 4 : Chromic acid CrO 3 + Aq. H 2 SO 4 + Acetone ─ Jones Oxidation CrO 3 + Pyridine ─ Saretts Oxidation CrO 3 + Pyridine + DCM ─ Collins Oxidation PDC: Pyridinium Dichromate PCC: Pyridinium Chlorochromate

3. H 2 CrO 4 (Chromic acid) CrO 3 + H 2 O/H 3 O + Na 2 Cr 2 O 7 /K 2 Cr 2 O 7 + H 2 SO 4 NaCrO 4 /KCrO 4 + H 2 SO 4 CrO 3 is a strong oxidizing agent that appears in the form of deep-red hygroscopic crystals. Unstable must be generated in situ .

4. Applications: 1 o alcohols ─ Acids (Over oxidized product) ii. 2 o alcohols ─ Ketones iii. Aldehydes ─ Acids

5. Mechanism:

6. Oxidation to carboxylic acids

7. Limitations: Primary alcohols always leads to carboxylic acids. Therefore it is not suitable for them. 3. Acid labile groups get opened in this oxidation process. For example. If alcohols having other oxidisable groups, those also get oxidized. For example.

8. Examples:

9. b. Jones Oxidation (CrO 3 + Aq. H 2 SO 4 + Acetone): Chromium trioxide is a strong oxidizing agent, and its use in organic synthesis had to overcome two problems: Its lack of solubility in most organic solvents. Its tendency to explode in the presence of organic matter. In 1946, Jones discovered that 2 o alcohols could be efficiently oxidized to ketones by pouring a solution of chromium trioxide in diluted sulfuric acid over a solution of the alcohol in acetone. This procedure, which has proved to be quite safe, allows a sufficient contact of the alcohol with chromium oxide derivatives for a reaction to take place. The action of sulfuric acid on chromium trioxide results in a number of equilibria, in which the major specie is chromic acid. Thus, Jones conditions are often referred as ‘ ‘chromic acid’’ in acetone. Sir Ewart Ray Herbert Jones (Organic Chemist, UK)

10. Jones oxidation is carried out under very convenient experimental conditions with no need to employ a dry environment or an inert atmosphere. Note: Safe method for the oxidation of alcohols. Applications: i . 1 o alcohols ─ Acids Useful yields of aldehydes can be obtained when the proportion of hydrate in equilibrium with the aldehyde is low. It rarely succeeds in the transformation of primary alcohols into aldehydes due to its tendency to cause over-oxidation to carboxylic acids. ii. 2 o alcohols ─ Ketones

11. Mechanism: Chromate ester Alcohol Chromous acid

12. Advantages and Limitations: Over oxidation product (acid) can be minimized in the case of 1 o alcohols using 1:1 ratio of CrO 3 . aq. H 2 SO 4 and alcohol (or) using less than 1 eq. of CrO 3 . aq. H 2 SO 4 comparing with alcohols. Unsaturated groups will not be effected. Using limited quantity of sulfuric acid helps to avoid removal of acid sensitive functional groups. On the other hand, this causes a decrease in the oxidizing power of Jones reagent. Note: The solution of the alcohol in acetone can be kept either over an ice-water bath or at room temperature during all the reaction. For reactions on a multigram scale, cooling on an ice-water bath is particularly recommended. During the oxidation of very sensitive substrates, it may be advisable to perform the entire oxidation at a temperature as low as – 20 o C.

13. Examples: Ethyl 3-hydroxypent-4-enoate

14. c. Sarett’s Oxidation (CrO 3 + Pyridine / CrO 3 . 2 Py ): When CrO 3 is added over pyridine, the complex CrO 3 .2Py is formed. This complex is soluble in most of the organic solvents. The complex, CrO 3 .2Py is highly hygroscopic and can explode during its preparation or in contact with organic matter. To use it in the oxidation of alcohols with the greater safety and experimental simplicity, in 1953 Sarett reported by adding CrO 3 to excess of pyridine results in the formation of a solution of the complex so-called Sarett reagent. This reagent is efficient for the transformation of alcohols into aldehydes and ketones.

15. Applications 1 o alcohols ─ Aldehydes 2 o alcohols ─ Ketones Advantages: No over oxidation products No effect on unsaturated double/triple bonds Acid labile groups unaffected Limitations: After oxidation, isolation of the product (carbonyl compound) in pure form from the pyridine solvent is difficult (Copper sulphate can be used to remove pyridine). The reagent is little expensive

16. Mechanism:

17. Example:

18. d. Collins Oxidation (CrO 3 . Pyridine + DCM): In 1968 , Collins was used pre-formed CrO 3 .2Py dissolved in DCM for the oxidation of alcohols, which became known as Collins oxidation . This method—although suffering from the inconvenience of handling highly hygroscopic CrO 3 .2Py—possesses the advantage over Saretts reagent of avoiding the use of pyridine as solvent. In 1970, Ratcliffe and Rodehorst described the in situ preparation of the complex CrO 3 .2Py by adding one equivalent of CrO 3 over a solution of two equivalents of pyridine in DCM. This variant of the Collins protocol , as it avoids the dangerous isolation and handling of the very hygroscopic complex CrO 3 .2Py, is nowadays greatly preferred. Very often, Celite is added to the Collins solution during the oxidation of alcohols in order to prevent loss of product in chromium precipitates.

19. Note: As CrO 3 is hygroscopic, care must be taken to avoid contamination with atmospheric moisture. Water must be avoided from the reaction mixture, for instance, with a CaCl 2 tube or with a blanket of an inert gas. The complete synthetic operations till the work-up can be made at room temperature or at 0 o C. Low temperature is particularly advisable on multigram reactions, at least during the initial mixing operations, in which greater exotherms are expected. It takes normally between 2 min and overnight. A quick quenching of the oxidation can be done by addition of aqueous Na 2 SO 3. Mechanism: Is same as Sarret’s oxidation.

20. Applications 1 o alcohols ─ Aldehydes 2 o alcohols ─ Ketones Advantages: After oxidation removal of DCM is easy. Therefore, carbonyl compounds in pure form can be obtained. No over oxidation products. No effect on unsaturated double/triple bonds. Acid labile groups unaffected.

21. Examples: Tr : Trityl ( Triphenyl methyl)

22. e. PDC: Pyridinium Dichromate (PDC in DCM or DMF: Corey-Schmidt reagent)

23. The slow addition of pyridine on a concentrated aqueous solution of CrO 3 leads to the formation of pyridinium dichromate (PDC). This can be precipitated by the addition of 4 volumes of acetone per volume of water and cooling at -20 o C as orange crystals. An explosion can occur during the preparation of PDC. This can be avoided by i ) Chromium trioxide must be completely dissolved in the concentrated aqueous solution. The temperature must be kept bellow 25 o C during mixing of the reagents. The use of PDC for the oxidation of alcohols was first described by Coates and Corrigan in 1969 . Nevertheless, full attention of the synthetic community for this useful reagent was achieved by the publication of E.J. Corey and Schmidt in 1979 .

24. PDC exists in the form of stable bright-orange crystals that remain unaltered by manipulation in the open air. Its lack of hydrophylicity and almost neutral properties facilitate its handling and allows the selective oxidation of alcohols in the presence of very sensitive functional groups. Although the presence of pyridinium cations makes PDC slightly acidic, very acid sensitive functionalities are able to withstand the action of PDC. Sodium acetate can be added as a buffer for a completely acid-free oxidation. Normally, the oxidation of alcohols to aldehydes or ketones is carried out using a suspension of PDC in DCM at room temperature. Other organic solvents, such as EtOAc , MeCN , benzene or CHCl 3 , are occasionally used. Sometimes, oxidations with PDC can be slow. However, the following chemicals can be added in order to achieve a synthetically useful acceleration. Molecular sieves (MS) An organic acid Acetic anhydride (in sugar and nucleoside chemistry)

25. Applications 1 o alcohols ─ Aldehydes 2 o alcohols ─ Ketones Advantages: No over oxidation products. No effect on unsaturated double/triple bonds. Acid labile groups unaffected. Easy to handle in laboratory. In expensive and readily available/purchased. Excellent reagent for the oxidation of allylic and benzylic alcohols.

26. Mechanism:

27. f. PCC: Pyridinium Chlorochromate (Corey-Suggs reagent) Addition of one equivalent of CrO 3 to 1.1 equivalents of HCl (6N) leads to a homogenous solution containing chlorochromic acid (ClCrO 3 H). Slow addition of one equivalent of pyridine to this solution at 0 o C , leads to the formation of pyridinium chlorochromate (PCC) that separates as yellow-orange crystals.

28. PCC was first prepared in 1899. But, its use in the oxidation of alcohols was started as late as in 1975, following a landmark publication by E.J. Corey and Suggs . Hence, the name Corey-Suggs reagent, often employed to refer PCC. Corey and Suggs described that most alcohols are oxidized in good yields to aldehydes and ketones using a suspension of PCC in DCM at room temperature. They also described the addition of NaOAc to the reaction mixture, in order to moderate the slightly acidic character of PCC. PCC is a stable solid of very moderate hydrophylicity that can be bought and stored for long periods without apparent decomposition.

29. Mechanism:

30. Examples:

31. Module-3, Lecture-7 Oxidation of Alcohols to carbonyls

32. Swern Oxidation Dr. Daniel Swern (American chemist)

33. DMSO Mediated Oxidations DMSO + DCC ( dicyclohexylcarbodiimide ) + Weak acid ( pyridinium trifluoroacetate /H 3 PO 4 /Cl 2 CHCOOH) – Pfitzner –Moffatt Oxidation DMSO + Ac 2 O – Albright–Goldman Oxidation DMSO + P 2 O 5 – Albright–Onodera Oxidation DMSO + SO 3 .Py – Parikh– Doering Oxidation DMSO + Trifluoroacetic anhydride (TFAA) – Omura –Sharma– Swern Oxidation (TFAA-Mediated Moffatt Oxidation) DMSO + ( COCl ) 2 + Triethylamine – Swern oxidation

34. Swern oxidation (DMSO + ( COCl ) 2 + Triethylamine ) According to Swern , oxalyl chloride is the most effective activator of DMSO . Probably they has tried the highest number of DMSO activators (e.g. Ac 2 O, P 2 O 5 , SO 3 .Py, Trifluoroacetic anhydride) for the oxidation of alcohols. It offers the advantage of quite consistent good yields in many substrates , with an operation performed under very low temperature and mild conditions. Thus, Swern oxidation has become the default oxidation method whenever activated DMSO is desired.

35. Applications: 1 o alcohol → aldehyde 2 o alcohol → Ketone

36. Mechanism: DMSO and oxalyl chloride react in an explosive manner at room temperature. As soon as, a drop of a solution of DMSO in DCM contacts a solution of oxalyl chloride in DCM at -60 o C , an almost instantaneous reaction takes place, resulting in the formation of chlorodimethylsulfonium chloride. The primary product ( sulfonium species ) decomposes very quickly even at -140 o C The activated DMSO molecule ( chlorodimethylsulfonium chloride) remains stable bellow -20 o C. Chlorodimethylsulfonium chloride decomposes above -20 o C to chloromethyl methyl sulfide via the reactive species H 2 C=S(+)-Me. chlorodimethylsulfonium chloride Sulfonium species

37. Activated DMSO Activated alcohol ( Alkoxy dimethylsulfonium chloride) - 60 o C to room temperature

38. Overall mechanism:

39. Advantages: Removal of byproduct is simple (CO 2 , CO, dimethyl sulfide - boiling point 37 o C ). Very high yield of the product. No over oxidation Unsaturated double and triple bonds unaffected. Acid labile groups unaffected. Limitations: Reactions have to be preformed at a very low temperature approximately -60 o C. At higher temperature the activated DMSO decomposes. At higher temperature the reaction is explosive. Solvents: DCM is almost exclusively used as the solvent. THF can be used rarely.

40. Examples:

41. Modified Swern Reagent: The standard Swern oxidation employing DMSO results in the formation of dimethyl sulfide, which is a toxic volatile liquid ( b.p . 38 o C ) with an unpleasant smell. This can be avoided by using other sulfoxides that generate sulfides lacking volatility such as; Sulfoxides containing perfluorated alkyl chains Sulfoxides bound to polymers such as polystyrene or poly(ethylene)glycol

42. Importance of these variants: These are not only avoid the generation of an unpleasant odour , but also facilitate the work-up. For example, 6-( Methylsulfinyl ) hexanoic acid generates a sulfide that is easily separated by chromatography. Fluorated sulfoxides produce sulfides that can be extracted with a fluorous solvent. Polymer-based sulfoxides generate sulfide-containing polymers that can be filtered. All these expensive sulfoxides can be regenerated by oxidation of the resulting sulfides using H 2 O 2 .

43. Reduction Reactions

44. Reduction: Addition of hydrogen or removal of oxygen from a substrate. 1. Hydride ion transfer reductions:

45. 2. Electron transfer reductions:

46. 3. Concerted reductions: Diimide reductions (N 2 H 2 ): b. Catalytic hydrogenation:

47. 1. Hydride ion Transfer Reducing agents Lithium aluminium hydride (LiAlH 4 ) White crystalline substance. Unstable. Reacts violently with water. Therefore, the reaction must and should carry out under anhydrous/inert conditions. Preparation: Solvents: Dry ethers, Et 2 O, THF

48. Applications: Highly reactive, versatile and a strong reducing agent due to the weaker Al-H bond, which capable of liberating H - . It reduces wide range of functional groups.

49. Almost all organic functions reduced by LAH. Applications: Carbonyl (-C=O) Acid (-COOH) Ester (-COOR) Acid halide (-COX) Cyclic ester Epoxides Amides (-CONR 2 ) Nitrile (-CN) Imine (-CH=NR) Azide (-CH 2 -N 3 ) Oxime (-C=N-OH) Nitro (-CH 2 -NO 2 ) LAH Alcohols LAH Amines LAH Hydrocarbons LAH trans olefins Halo compounds (R-X) Alkyl sulfonates (R-SO 3 R 1 ) Propargyl alcohols/ethers Simple isolated olefins, alkynes and ethers would not reduced by LAH. However, the double or triple bonds in conjugation with the polar multiple bonds can be reduced.

50. Mechanism: With carbonyl compounds

51. Alkoxy groups exerts – I effect on Aluminium . With increasing in no. of alkoxy groups, – I effect become stronger on Aluminium hydride as a result the reactivity decreases as the alkoxy groups increases. Reactivity order: LiAlH 4 > LiAl (OR)H 3 > LiAl (OR) 2 H 2 > LiAl (OR) 3 H > LiAl (OR) 4 Mechanism: With Esters

52. Mechanism: With Acid Mechanism: With Acid chloride

53. Mechanism: With cyclic ester Mechanism: With amide

54. Mechanism: With Nitrile Mechanism: With Azide

55. Stereochemical Aspects: In opening of epoxides and reduction of halo compounds - SN 2 addition and Inversion of configuration can be observed.

56. In confirmationally rigid molecules, opening of epoxides by attacking in axial direction.

57. Reduction of rigid cyclohexanone derivatives: Axial and equatorial approaches are free form steric crowding in the above examples. Thus selectivity is controlled by the stability of the product.

58. In the case of aromatic α , β -unsaturated aldehydes, product depends on the reaction conditions. In amides, if “ N ” is a part of heterocyclic ring. In LAH reduction products are aldehyde and amines. But, cyclic amide converts to amines.

59. How to quench LiAlH 4 : Fieser method: For a reaction containing x grams of LAH 1. Cool the reaction mixture to 0 °C (or lower depending on the scale/equivalents of LAH) 2. Slowly (drop wise) add x mL of water 3. Add x mL of 15% aqueous sodium hydroxide (or potassium hydroxide). 4. Add 3x mL of water 5. Warm the reaction mixture to room temperature and stir for 30 min 6. Filter and wash the solid with ether 2 - 3 times 7. Collect the filtrate and evaporate the solvent using rotary evaporator.

60. Module-3, Lecture-8

61. (b) Sodium Borohydride (NaBH 4 ) White crystalline Solid. In aqueous medium stable, therefore water can also be used as a solvent Solvents: Water and alcohols like MeOH , EtOH , Isopropanol and tertary butanol etc . Therefore, LiAlH 4 releases H - rapidly. Whereas NaBH 4 releases H - slowly. Means the reactivity of NaBH 4 lesser than LiAlH 4. 1. Hydride ion Transfer Reducing agents

62. Applications: Carbonyl (-C=O) Ester (generally not reactive but in the presence of additives like Iodine) Imine Iminium salts Alcohols Alcohols Amine Amine In a molecule, if aldehyde and ketones are present at lower temperature (-78 o C ) NaBH 4 selectively reduces aldehyde but not ketone.

63. In the case of aromatic α , β -unsaturated carbonyl compounds, even at higher temperature NaBH 4 reduces only carbonyl functions into alcohols. Unsaturation unaffected. Mechanism:

64. Alkoxy groups exerts + Mesomeric effect (+M.E) on Boron. With increasing in no. of alkoxy groups, +M.E effect become stronger on boron hydride as a result the reactivity increases as the alkoxy groups increases. Reactivity of alkoxy NaBH 4 in reduction reverse to LiAlH 4 Reactivity order: LiAlH 4 > LiAl (OR)H 3 > LiAl (OR) 2 H 2 > LiAl (OR) 3 H > LiAl (OR) 4 NaB (OR) 4 > NaB (OR) 3 H > NaB (OR) 2 H 2 > NaB (OR)H 3 > NaBH 4 Reason for difference in reactivity order:

65. Empty orbital of Boron and occupied orbitals of oxygen energetically closer which allows strong overlapping. Transfer of electron cloud from oxygen to Boron + M effect. Hence increases the reactivity. Empty orbital of Aluminium and occupied orbitals of oxygen are belongs to the different shells. Therefore poor overlapping, weak in strength of + M effect. In preference to +M effect, alkoxy oxygen exerts –I effect which decreases the reactivity of Alkoxy aluminium hydrides. Alcohols little enhances rate of NaBH 4 reductions by establishing H-bond with carbonyl oxygen.

66. Stereochemical aspects of NaBH 4 : Same as LiAlH 4 , NaBH 4 also attacks at sterically less crowded side of the carbonyl function.

67. Keto carbonyl oxygen is good nucleophile than aldehyde carbonyl oxygen. Therefore, the keto carbonyl oxygen preferentially coordinate with Ce ion. Similarly in the case of conjugated carbonyl also. Luche’s Reduction: NaBH 4 + CeCl 3 . 6H 2 O (cerium(III) chloride hexahydrate ) NaBH 4 in combination with Ce(III) salts selectively reduces less reactive carbonyl groups in carbonyl compounds. Ketones are less reactive than aldehydes Conjugated carbonyl are less reactive than isolated carbonyls.

68. With keto carbonyl oxygen makes carbonyl carbon more electron deficient than competitive more reactive carbonyl carbon. Approaching nucleophile selectively attacks more electron deficient carbonyl carbon. As the results selective reduction of less reactive carbonyl by leaving behind more reactive carbonyls. Examples:

69. (c) Sodium Cyano Borohydride ( NaBH₃CN ) Functions: Under neutral conditions (pH ≈ 7), selectively displaces Halo and Tosyloxy groups. Any other functional groups like carbonyl, epoxy etc. are unaffected. Cyano electron withdrawing group stabilizes borohydride. Compare to NaBH 4 , NaBH₃CN is less reactive and more selective in reduction. Reactivity of NaBH₃CN depends on pH of the reaction medium (neutral/acidic/basic).

70. At pH ≈ 2-3, reduces carbonyl into alcohols. At pH ≈ 5-6, reduces imines into amines. In acidic medium, tosyl hydrazones of acylic and cyclic carbonyl compounds reduces into hydrocarbons. In acidic medium, opens epoxide into alcohols – Opens at sterically more crowded position. Applications:

71. Examples: Whenever carbonyl function is in conjugation with α , β -unsaturation, isomerization of unsaturation takes place. Hexamethylphosphoramide (HMPA)

72. Mechanism for isomerization:

73. 2. Electron Transfer Reducing agents Metal/Acid (or) Metal/Base Metals d-block – Fe, Sn etc. I group: Li, Na, K II group: Ca, Mg

74. Metal-Base Medium Reactions Metals: I group - Li, Na, K; II group: Ca, Mg Bases: Liq. NH 3 (or) R-NH 2 Solvents: Dry ethers: Et 2 O, THF, Dioxane Electron released in liq. Ammonia is called as solvated electrons. Applications: Conjugated olefins → Isolated olefins Aromatic hydrocarbons → Unconjugated olefins (or) 1,4-dihydro products Simple carbonyl compounds → Alcohols α , β -unsaturated carbonyl compounds → Saturated alcohols (or) Saturated carbonyl compounds (or) Unsaturated alochols Alkynes → Trans Olefins

75. i . Reduction of Conjugated olefins → Isolated olefins Mechanism:

76. ii. Reduction of Aromatic hydrocarbons: Birch Reduction Mechanism:

77. Regioselectivity : Substitution effect Mechanism: Aromatic hydrocarbon containing electron donating group

78. Mechanism: Aromatic hydrocarbon containing electron withdrawing group. Examples: