INORGANIC REAGENTS FOR ORGANIC SYNTHESIS

INORGANIC REAGENTS FOR ORGANIC SYNTHESIS

1. B.Sc. Sem-V Organic Chemistry (Che-301) Presentation By Dr. Nandan C. Pomal Assistant Professor, Faculty Of Science, Sigma University, Vadodara, Gujarat Unit-II (A) Inorganic Reagents For Organic Synthesis

2. ALUMINIUM ISOPROPOXIDE Aluminium Isopropoxide [(CH3) 2 CHO - ] 3 Al 3+ It is used as catalysts and an intermediates in a different reactions. They belong to aluminum alkoxide groups. Widely used as a selective reducing agent for aldehydes and ketones. It is an inexpensive and also easy to handle among the other aluminum alkoxides.

3. ALTERNATIVE NAMES Triisopropoxyaluminium Aluminiumisopropanolate 2-Propanol aluminium salt AIP

4. STRUCTURE OF ALUMINIUM ISOPROPOXIDE The central Aluminium is octahedral surrounded by three bidentate (O- iPr ) 3 ligands, each featuring tetrahedral Al.

5. PHYSICAL PROPERTY More soluble in benzene and less soluble in alcohols White solid Boiling point : 140.5 C Melting point : 128 -133 C It decomposes in presence of water

6. HANDLING, STORAGE, AND PRECAUTIONS The dry solid is corrosive Moisture sensitive Flammable An irritant Used in a fume hood

7. PREPARATION It is prepared by the reaction between isopropyl alcohol and aluminium metal, or aluminium trichloride: 2 Al + 6 iPrOH → 2 Al(O- i -Pr)3 + 3 H2 AlCl3 + 3 iPrOH → Al(O- i -Pr)3 + 3 HCl

8. SYNTHETIC APPLICATION MEERWEIN-PONNDORF-VERLEY (MPV) REDUCTIONS Carbonyl compound are reduced to the respective alcohol in the presence of aluminium isopropoxide solution. The acetone, so formed, is removed by slow distillation and hence the reaction proceeds only in the desired direction.

9. Reaction

10. Mechanism STEP (1) The aluminium alkoxide 1, reacted with a carbonyl oxygen to form tetra coordinated aluminium intermediate 2 STEP (2) The intermediates 2 transfer hydride to the carbonyl group from the alkoxy ligand to form an another intermediate 3 STEP (3) The intermediate 3 eliminate a new carbonyl group and gives a tricoordinate aluminium species 4. STEP (4) Alcohol is formed and the catalyst 1 is regenerated.

11. Example ii) Reduction of o- nitrobenzaldehyde to o- nitrobenzyl alcohol a) Reduction of aldehyde i ) Reduction of crotonaldehyde to crotyl alcohol

12. b) Reduction of ketone i) Synthesis of oestradiol from oestrone

13. OPPENAUER OXIDATION It is an oxidation reaction of alcohol to ketone in presence of aluminium isopropoxide.

14. Example: Cholestenone is prepared by oxidation of cholesterol in toluene solution with aluminum isopropoxide as catalyst and cyclohexanone as hydrogen acceptor.

15. • Conversion of carvone to carveol

16. HYDROLYSIS OF OXIMES Oximes can be converted into parent carbonyl compounds by aluminum isopropoxide followed by acid hydrolysis.

17. Lithium aluminium hydride (LIALH 4 )

18. Lithium Aluminium Hydride LiAlH 4 is a reducing agent . More specifically, nucleophilic reducing agent and used to reduce polar multiple bonds like C=O. There is a tetrahedral arrangement of hydrogens around Al 3+ in aluminium hydride, AlH 4- ion. The hybridization in central Al is sp 3 . LiAlH 4

19. Lithium Aluminium Hydride : Physical Property Reacts with water, soluble in THF and miscible with diethyl ether White crystals solid (pure samples) appearance grey powder (commercial material) hygroscopic Boiling point : 184 ° C, Melting point : 150 ° C Density: 0.917 g/cm 3 (solid) It is odourless

20. Lithium Aluminium Hydride: Preparation LAH is prepared by the reaction between Lithium Hydride and Aluminium Chloride . LiAlH 4

21. Lithium aluminium hydride: Chemical Properties LiAlH 4 It reacts violently with water by producing hydrogen gas and therefore it should not be exposed to moisture and the reactions are performed in inert and dry atmosphere. ( anhydrous non-protic solvents ) 2. As far as the preference of solvent is concerned, it is highly soluble in diethyl ether. However it may spontaneously decompose in it due to presence of catalytic impurities. Therefore the  preferred solvent for LAH is THF despite the low solubility.

22. Lithium Aluminium Hydride Mechanism of reduction The reduction of a carbonyl group by LiAlH 4 is initiated by the attack of nucleophilic hydride ion on the carbonyl carbon to give a tetrahedral intermediate. LiAlH 4 is a nucleophilic reducing agent since the hydride transfer to the carbonyl carbon occurs prior to the coordination to the carbonyl oxygen. It reacts faster with electron deficient carbonyl groups. The reactivity of carbonyl compounds with this reagent follows the order: LiAlH 4 Aldehydes > Ketones > Ester > Amide > Carboxylic acid

23. LAH: Mechanism of reduction Mechanism of Reduction of carbonyls to alcohols: A hydride ion is transferred onto the carbonyl carbon and the oxygen atom coordinates to the remaining aluminium hydride species to furnish (I) , which can reduce 2 more carbonyl molecules. LiAlH 4 (three of the hydride ions are used up) (I) Alkoxytrihydroaluminate ion

24. Lithium aluminium hydride: Applications LiAlH 4 Substrate Product Aldehyde Primary alcohol Ketone Secondary alcohol Carboxylic acids Primary alcohol Esters Primary alcohol Amides Amines Nitriles Amines Epoxides Alcohols Lactones Diols

25. Lithium aluminium hydride: Applications Lithium aluminium hydride, LAH reagent cannot reduce an isolated non-polar multiple bond like C=C . However, the double or triple bonds in conjugation with the polar multiple bonds can be reduced. LiAlH 4

26. LAH: Applications 1) Reduction of carbonyl compounds using LiAlH 4 : LiAlH 4

27. … LAH: Applications … Reduction of carbonyl compounds using LiAlH 4 : LiAlH 4

28. … LAH: Applications Stereochemistry: The axial attack of hydride ion is preferred over the equatorial attack in case of cyclic systems. For example, 4-t-butylcyclohexanone yields more than 90% of trans -4-t-butylcyclohexanol when reduced with LAH. LiAlH 4

29. … LAH: Applications The plausible explanation for this behavior is: the -OH group prefers the equatorial position to avoid the interactions with other axial hydrogens. i.e., It is not the approach of hydride ion but the orientation of -OH group which decides the final stereochemistry. LiAlH 4

30. … LAH: Applications 2) The carboxylic acids, acid halides and esters are reduced to corresponding primary alcohols. LiAlH 4

31. … LAH: Applications 3) The amides are reduced to amines. 4) The nitriles are reduced to primary amines. LiAlH 4

32. … LAH: Applications 5) LAH reduces the oxiranes (epoxides) to alcohols. The mechanism involves hydride attack at less hindered side of the epoxide. LiAlH 4

33. … LAH: Applications 6) The lactones are reduced to α,ω-diols by LiAlH 4 . 7) The haloalkanes and haloarenes are reduced to corresponding hydrocarbons . LiAlH 4

34. 2 SeO 2 : Structur e Ø   Selenium dioxide is a colorless solid . It exists as one dimensional polymeric chain with alternating selenium and oxygen atoms. Ø   It sublimes readily and hence the commercial samples of SeO 2 can be purified by sublimation. Ø   SeO 2 is an acidic oxide and dissolves in water to form selenous acid, H 2 SeO 3 .

35. 3 Selenium dioxid e Ø   Selenium dioxide, SeO 2 is an oxidizing agent generally employed in the allylic oxidation of alkenes to furnish allylic alcohols , which may be further oxidized to conjugated aldehydes or ketones. Ø   It is also used to oxidize the α-methylene group adjacent to a carbonyl group to give a 1,2-dicarbonyl compound . However selenium dioxide can perform several common types of oxidations, such as alcohols to ketone s or aldehydes. Ø   The oxidations of methylene groups using Selenium dioxide are referred t o as Riley oxidations .

36. 4 Selenium dioxid e

37. 5 SeO 2 : Properties Reaction conditions: Ø   Compounds of selenium are very poisonous and smell y . Hence the reaction setup must be maintained under a fuming cupboard. Ø   Use of acetic acid as solvent stops the reaction at allylic alcohol stage due to formation of acetate esters. Ø   A convenient way to carry out the reaction is to use only a catalytic amount of SeO 2 along with an oxidizing agent like t-butyl hydroperoxide , that reoxidizes the selenium(II) compounds after each cycle of the reaction. This eliminates the need to get rid of la r ge amounts of selenium compounds, which are toxic and usually smell y . Ø   It also ensures the principal product is allylic alcohol by reducing the chances of further oxidation to conjugated carbonyl compounds. W orkup: Ø   The final workup involves precipitation of selenium or selenium compounds, whic h can be filtered o f f before isolation of product from the reaction mixture.

38. 6 SeO 2 : Applications 1. Allylic oxidation of alkenes: Selenium dioxide oxidizes allylic positions to alcohol or carbonyl groups. It starts with Alde r -ene like 4+2 cycloaddition of SeO 2 to give an allylic selenic acid that further unde r goes [2,3]-sigmatropic rearrangement to give an unstable compound that may decompose to allylic alcohol or an allylic carbonyl compound as shown belo w .

39. 7 SeO 2 : Examples i.   Catalytic amount of selenium dioxide and t-BuOOH can be employed in the allylic oxidation of cyclohexene to cyclohex-2-en-1-ol, an allylic alcohol. ii.   T risubstituted alkenes are oxidized selectively at more substituted end o f double bond by giving E-allylic alcohols or conjugated carbonyl compounds predominantl y .

40. 8 SeO 2 : Examples

41. 9 SeO 2 : Examples It is because the initial ene type 4+2 cycloaddition involves preferential attack of the more nucleophilic end of double bond at selenium . In this step, alkene uses the π- HOMO to attack the π*-LUMO of Se=O. Meanwhile the π-HOMO of Se=O attacks the σ*-LUMO of C-H of the allylic system. The E-selectivity is due to cyclic nature of final [2,3] sigmatropic step in which the alkyl substituent adopts pseudoequatorial position .

42. 10 SeO 2 : Examples iii.   The allylic oxidation occurs predominantly at most nucleophilic double bond. In the following example, no allylic positions of double bond nearer to electron withdrawing acetyl group are oxidized. i v .   It also oxidizes benzylic methylene, CH 2 group to C=O.

43. 11 SeO 2 : Examples

44. 12 SeO 2 : Mechanism 2. Formation of 1,2-dicarbonyl compounds f r om carbonyls: SeO 2 can also oxidize α-methylene group on a carbonyl compound to furnis h 1,2-dicarbonyl compound. The mechanism involves steps similar to allylic oxidation. adichemistr y .com

45. 13 SeO 2 : Examples i.   Acetophenone can be oxidized with SeO 2 to oxo(phenyl)acetaldehyde, a 1,2-dicarbonyl compound. Semperviridine : Gribble, G. W .; Barden, T . C.; Johnson, D. A. T etrahed r on Lett. 1988 , 44 , 1988 ii.   Dicarbonyls;

46. 14 Selenium dioxid e 3. The internal alkynes a r e converted to 1,2-dicarbonyl compounds whe r eas terminal alkynes a r e oxidized to glyoxylic acids: Selenium oxide can also be used to oxidize alkynes in presence of acids.

47. 15 SeO 2 : Summary Applications 1 . Allylic oxidation of alkenes 2 . Formation of 1,2-dicarbonyl compounds f r om carbonyls 3 . Internal alkynes a r e converted to 1,2-dicarbonyl compounds, whe r ea s terminal alkynes a r e oxidized to glyoxylic acids.

48. 2 Osmium tetroxid e Ø   OsO 4 form monoclinic crystal. It has a characteristic acrid (pungent ) chlorine like odou r . Ø   The element name osmium is derived from osme, Greek for odo r . Ø   OsO 4 is colorless, but most samples appear yello w . This is most likely due to the presence of the impurities of OsO 2 . ü   It is volatile in nature: sublimes at room temperature. ü   The compound is noteworthy for its many uses , despite its toxicity and rarity of Osmium.

49. 4 OsO 4 : Physical properties Ø   Soluble in wide range of o r ganic solvents. Ø   Moderately soluble in water (6.2 g/100 ml), with which it reacts reversibly to form osmic acid. Ø   It is tetrahedral and therefore non-pola r . Ø   Osmium is the densest (density 22.59 gcm -3 ) transition metal naturally available. Ø   M. P . 40 °C. Ø   Sublimes at R T . Ø   B. P . 130 °C.

50. 5 OsO 4 : Preparation Ø   Formed slowly when osmium powder reacts with O 2 at ambient temp. Ø   Reaction of bulk solid requires heating to 400 ° C. Os + 2O 2 → OsO 4

51. 6 OsO 4 : Applicatio n 1.   Dihydroxylation of alkenes 2.   Sharpless Asymmetric Dihydroxylation 3.   Lemieux-Johnson oxidation 4.   Reaction with Alkynes

52. 7 OsO 4 : Applicatio n 1. Dihyd r oxylation of alkenes: Alkenes add to OsO 4 to give diolate species that hydrolyze to cis-diols via [3+2] cycloaddition. The net proces s is called dihydroxylation . The reaction proceeds through an intermediate osmate ester which rapidly hydrolyses to yield the vicinal diol.

53. 8 OsO 4 : Applicatio n NPTE L – Chemistry

54. 9 ü   The use of tertiary amine such as triethyl amine or pyridine enhances the rate of reaction. OsO 4 : Applicatio n NPTE L – Chemistry

55. 10 ü   Catalytic amount of OsO 4 can be used along with an oxidizing agent, which oxidize s the reduced osmium(VI) into osmium(VIII) to regenerate the catalyst . ü   A variety of oxidizing agents, such as hydrogen peroxide, metal chlorates, tert -butyl hydroperoxide, N -methylmorpholine- N -oxide, molecular oxygen, sodium periodate and sodium hypochlorite, have been found to be e f fective. OsO 4 : Applicatio n NPTE L – Chemistry

56. 11 OsO 4 : Applicatio n NPTE L – Chemistry

57. 12 OsO 4 : Applicatio n NPTE L – Chemistry

58. 13 OsO 4 : Applicatio n ü   OsO 4 is widely used to oxidize alkenes to the vicinal diols, adding two hydroxyl groups at the same time (syn addition). ü   This reaction has been made both catalytic ( Upjohn dihydroxylation ) an d asymmetric ( Sharpless dihydroxylation ). OsO 4 Upjohn Sharpless

59. Lead tetra acetate ( Criegee Reagent )

60. 2 Lead tetra acetate ( Criegee Reagent ) ü   Lead tetraacetate ( L T A) is one of the powerful common oxidizing reagent s available with wide applications for o r ganic synthesis. ü   The reagent is very toxic, hygroscopic and turns brown due to lead dioxide formation on exposure to ai r . Therefore, the reagent is to be handled with extreme care in a chemical hood . ü   It can be prepared by adding red lead oxide, Pb 3 O 4 , to a mixture of acetic acid and acetic anhydride at ~70 o C.

61. 3 Lead tetra acetat e 1. Reaction with Alcohols Ø   L T A oxidizes alcohols to aldehydes and ketones in the presence of pyridine at ambient temperature. The reactions are e f ficient and over oxidation t o carboxylic acids are not observed . Ø   For example, pentanol and cinnamyl alcohol can be oxidized to give aldehydes in the presence of pyridine with high yield.

62. 4 Lead tetra acetat e ü   In the case of 1,2-diols, oxidative cleavage is observed to give aldehydes, ketones or both depending on the structure of the diols. ü   The reaction involves a cyclic intermediate and cis- 1,2 - diols exhibit greater reactivity compared to trans- 1,2-diols. ü   The reactions are performed in o r ganic solvent such as benzene, toluene, dichloromethane (DCM) and tetrahydrofuran ( TH F) . ü   When three or more hydroxyl groups are present on adjacent carbon atoms, then the middle one is converted into formic acid .

63. 5 …Lead tetra acetat e Ø   Cis -diols are cleaved more readily compared to trans diols. Di f ferent mechanistic interpretations are thus proposed for the two processes.

64. 6 Lead tetra acetat e

65. 7 Lead tetra acetat e

66. 8 Lead tetra acetat e 2. Cyclization of Saturated Alcohols Ø   The alcohols having δ-hydrogen unde r goes cyclization in presence o f L T A via a radical pathway to give tetrahydrofuran.

67. 9 …Lead tetra acetat e . a b c d

68. 10 Lead tetra acetat e ü   Reaction of the alcohols with L T A may give the intermediate a , which ca n unde r go thermal or photochemical homolytic cleavage to give alkoxy radical b . ü   The intermediate b may then lead to the formation c via abstract of δ hydrogen abstraction, which may react with Pb(OAc) 3 to give d . ü   The Pb(III)-alkyl compound then unde r goes heterolytic cleavage of C-P b bond to generate alkyl carbocation that forms the cyclic ether by reactio n with hydroxy group.

69. 11 …Lead tetra acetat e 3. Reactions of Carboxylic Acids Ø   Generall y , the carboxylic acids with L T A unde r go decarboxylation to give products such as esters, alkenes.

70. 12 Lead tetra acetat e

71. 13 …Lead tetra acetat e Howeve r , when a double bond is located nearb y , lactone is obtained

72. 14 Lead tetra acetat e 4. Acetoxylation Ø   Ketones unde r go reaction with L T A to give acetylated products at alpha- position. The yield can be improved with catalytic amount of BF 3 .

73. 15 Lead tetra acetat e 5. Dehyd r ogenation Ø   Aliphatic amines readily unde r go reaction with L T A to give nitriles , while the reactions of N,N’-disubstituted hydrazines a f ford azo compounds. These reaction conditions are e f fective for the oxidation of 4,4’-dihydroxybiphenyl to a f ford diphenoquinone .

74. 16 …Lead tetra acetate: Summary Ø   Applications: 1.   Reaction with Alcohols 2.   Cyclization of Saturated Alcohols 3.   Reactions of Carboxylic Acids 4.   Acetoxylation 5.   Dehydrogenation