REACTION MECHANISM REACTION MECHANISM. ppt

REACTION MECHANISM

1. REACTION MECHANISMS Sidra Siddique

2. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

3. 1. Arndt- Eistert reaction

4. Arndt- Eistert reaction The Arndt- Eistert Synthesis allows the formation of homologated carboxylic acids or their derivatives by reaction of the activated carboxylic acids with diazomethane and subsequent Wolff-Rearrangement of the intermediate diazoketones in the presence of nucleophiles such as water, alcohols, or amines

5. Named for the German chemists Fritz Arndt (1885–1969) and Bernd Eistert (1902–1978). The  Arndt– Eistert synthesis is a series of chemical reactions designed to convert a carboxylic acid to a higher carboxylic acid homologue (i.e. contains one additional carbon atom) and is considered a homologation process. Arndt– Eistert synthesis is a popular method of producing β- amino acids from α- amino acids. Acid chlorides react with diazomethane to give diazoketones . In the presence of a nucleophile (water) and a metal catalyst (Ag 2 O), diazoketones will form the desired acid homologue.

6. General equation

7. Reaction Mechanism 1) Activation of Carboxylic Acid  Conversion of carboxylic acid to an active compound like acid chloride or an anhydride. R-COOH + SOCl 2   --------> R- COCl + SO 2  + HCl 2) Formation of α- Diazoketone   Conversion of acid chloride to a diazoketone . A base like Et 3 N is employed to neutralize HCl liberated in this step. R- COCl +  CH 2 N 2   --------> R-CO CH N 2  + HCl

8. Ag 2 O, Δ or hν, -N 2 Nucleophile (Nu) R-CO CH N 2  ------------------------------------->   R- CH =C=O  -------------------------------->  R- CH 2 CONu diazoketone Wolff rearrangement ketene higher homologue 3) Wolff rearrangement The  Wolff rearrangement  of diazoketone into a ketene and subsequent conversion of it to a higher carboxylic acid or its derivative by using a nucleophile. * Nucleophile (Nu) = water or alcohol or amines

9. EXAMPLE Acetic acid                    Propionic acid

10. APPLICATIONS Arndt- Eistert reaction is used for homologation of carboxylic acids and homologated acid derivatives such as amides and esters.  This reaction is widely used nowadays for the synthesis of β-amino acids from α- amino acids. This reaction is employed in the synthesis of papaverine (a vasodilator) and mescaline (causes euphoria).

11. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

12. 2.Baeyer-Villiger oxidation

13. The  Baeyer–Villiger oxidation  is an organic reaction that forms an ester from a ketone or a lactone from a cyclic ketone, using peroxyacids or peroxides as the  oxidant. The reaction is named after  Adolf von Baeyer and Victor Villiger  who first reported the reaction in 1899 . This reaction is also called Baeyer-Villiger rearrangement reaction .

14. The Baeyer-Villiger oxidation is an organic reaction used to convert a ketone to an ester using a peroxyacid . The reaction of the ketone with the acid results in a tetrahedral intermediate, with an alkyl migration following to release a carboxylic acid. The more electron rich R group migrates to the oxygen in this concerted process, allowing for accurate prediction of the stereochemistry of the product

15. General Equation

16. Reaction Mechanism Step-1: Protonation  The peroxyacid protonates the carbonyl oxygen of  ketone .  Step-2 : Nucleophilic Addition The peroxyacid acts as a nucleophile and attacks the carbon of the carbonyl group forming an adduct ( Criegee intermediate).  Step-3: Rearrangement Through a concerted mechanism, one of the substituents on the ketone (R2) migrates to the oxygen of the peroxide group while carboxylate leaves . Step-4:  Deprotonation   In final step, proton shift results in product formation i.e., ester and carboxylic acid. 

17. Examples Oxidation of acetophenon Oxidation of benzophenon

18. Applications Baeyer-Villiger oxidation reaction is used for the synthesis of esters from ketones. Ester product can be further   hydrolyzed   to get a carboxylic acid. This reaction is used for the preparation of lactones from cyclic ketones. This reaction is used for the preparation of anhydrides from alpha- diketones . This reaction is also used for synthesis of pharmaceutical drugs. Examples are synthesis of steroidal anticancer drug testololactone  , and synthesis of zoapatanol . 

19. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

20. 3.Diels Alder reaction

21. The Diels–Alder reaction is the reaction between a conjugated diene and an alkene ( dienophile ) to form unsaturated six-membered rings. Since the reaction involves the formation of a cyclic product via a cyclic transition state, it is also referred to as a " cycloaddition ". The Diels–Alder reaction is an electrocyclic reaction, which involves [4+2]‑ cycloaddition of 4 π-electrons of the conjugated diene and 2 π-electrons of the dienophile (an alkene or alkyne). The reaction involves the formation of new σ-bonds, which are energetically more stable than the π-bonds. This reaction has great synthetic importance and was discovered by two German chemists, Otto Diels and Kurt Alder in 1928. They were awarded the Nobel Prize in 1950 .

22. General Equation A Diels-Alder reaction brings together two components. One part we call the “ diene “, which is comprised of two adjacent (i.e.  conjugated ) pi bonds. The second component is called the “ dienophile “, which is to say “ diene -loving”, and has at least one pi-bond.

23. Reaction Mechanism The Diels-Alder reaction is a concerted Reaction this means it occurs in only one   Step. Moreover, all of the atoms that are participating in the reaction form bonds simultaneously through a cyclic transition state

24. Examples

25. Applications Diels-Alder reaction provides a reliable way to form six-membered rings.  Diels-Alder reaction has been applied in the total synthesis of the steroid hormones  ;cortisone and cholesterol.   Reserpine is a naturally occurring alkaloid  and is used for the treatment of hypertension and psychiatric disorders. Total synthesis of this natural compound involves Diels-Alder reaction.   The Diels–Alder reaction is also employed in the production of vitamin B6 (Pyridoxine). 

26. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

27. 4. Grignard’s reaction

28. A Grignard reagent is a magnesium-containing compound with the general formula RMgX , where R is an alkyl or aryl group and X is a halogen, typically chlorine, bromine, or iodine. The R group can be a variety of hydrocarbon chains or rings, including aromatic rings . Grignard reagents are named after their discoverer, French chemist Victor Grignard, who first prepared them in the early 20th century. They are highly reactive and versatile reagents that can form carbon-carbon and carbon-heteroatom bonds, making them essential cornerstone of organic synthesis, with applications in the preparation of complex molecules, including natural products, pharmaceuticals, and materials.

29. PREPARATION : Magnesium can be reacted with alkyl halides or aryl halides to form grignard reagent. The organic halide is added to a magnesium suspension in an ether solvent. It is important to note that the Reagent can be made with alkyl chlorides, bromides, and iodides but not with fluorides.

30. The origin of the Grignard reaction is the great imbalance of electron distribution. On the one hand, we have the  C-Mg non-metal-metal polar bond which is almost ionic,  and on the other hand, we have the  C=O bond  where the electron density is on the oxygen and the  carbon is highly electrophilic When these two are mixed, the strongly Grignard reagent uses the  C-Mg electron pair to form a bond to the carbon atom  of the carbonyl. This nucleophilic attack pushes the electronpair of the carbonyl π bond to the oxygen forming an alkoxide . The resulting alkoxide ion associated with Mg 2 ­ and the halide is then neutralized by reacting with water or an acid

31. General Equation

32. REACTION MECHANISM The Grignard reaction occurs in two steps: The nucleophilic R group attacks the electrophilic carbonyl A weak acid, often water, is added to hydrogenate the oxygen, forming an alcohol It is important for water to be added after the Grignard reagent reacts with the carbonyl. If water is added first, then the Grignard reagent will react primarily with the water, as a base, and deactivate the Grignard reagent so no new carbon-carbon bonds form with the carbonyl . A Grignard reagent is an extremely powerful nucleophile and can react with electrophiles like carbonyl compounds.

33. Examples

34. https://www.chemistryscl.com/advancedlevel/organic/grignard/main.html

35. Applications Grignard reagents are best for the preparation of amides, acetals , amino compounds, organosulphur compounds, ethers, ketones, aldehydes, etc. It can be used for the production of several compounds that has a very important application in the pharmaceutical, perfume, and specialty chemicals field. Grignard reagents can be used to produce alcohol from epoxides. Grignard reagent reaction with aldehyde ketone and esters to form alcoholic compounds. It can be used for the synthesis of many organometallic compounds.

36. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

37. 5. Metal Hydride reduction

38. Definition: Metal hydride reduction is a chemical reaction in organic chemistry where metal hydrides, such as lithium aluminum hydride (LiAlH4) or sodium borohydride (NaBH4), are used as reducing agents to convert carbonyl compounds (aldehydes or ketones) into their corresponding alcohols. Basic Concept: Metal hydrides act as a source of hydride ions (H⁻), which are strong reducing agents capable of donating a hydride ion to the carbonyl carbon of the substrate. The hydride ion attacks the electrophilic carbon atom of the carbonyl group, resulting in the formation of an alkoxide intermediate. This intermediate is subsequently protonated by water or an acid to yield the alcohol product. The reaction proceeds via a nucleophilic addition-elimination mechanism, resulting in the reduction of the carbonyl group to a hydroxyl group.

39. Two valuable reducing agents commonly used are lithium aluminum hydride (LAH) and sodium borohydride (NBH). Both reduce aldehydes and ketones to alcohols. These two metal hydrides are quite different in their reactivities . LiAlH4 is a powerful reducing agent that reduces not only aldehydes and ketones, but also carboxylic acids, esters, amides, and nitriles . LiAlH4 undergoes violent reaction with water, therefore reductions are usually carried out in a solvent such as anhydrous ether . NBH is a milder reducing agent than LAH. Its reactions can be carried out in water or aqueous alcohol as a solvent. For the reduction of aldehyde or ketone, NaBH4 is the preferred reagent; it is certainly more convenient to use because of its lower reactivity towards water. NaBH4 reduces aldehydes and ketones rapidly while it reduces esters slowly. Therefore, an aldehyde or ketone carbonyl group can be reduced without the simultaneous reduction of an ester group in the same molecule. This selectivity is not possible with LAH.

40. General Equation

41. Reaction Mechanism Step-1: Metal hydrides react by transferring a negative hydride ion to the positive carbon of a carbonyl group . Step-2 : Protonation of alkoxide

42. Each hydride ion can reduce one carbonyl group. Therefore, one mole of NaBH4 can reduce four moles of aldehydes or ketones . Addition of a hydride anion (H: - ) to an aldehyde or ketone gives an alkoxide anion, which on protonation yields the corresponding alcohol. Aldehydes produce 1º-alcohols and ketones produce 2º-alcohols . In metal hydrides reductions, the resulting alkoxide salts are insoluble and need to be hydrolyzed (with care) before the alcohol product can be isolated. In the sodium borohydride reduction the methanol solvent system achieves this hydrolysis automatically. In the lithium aluminum hydride reduction water is usually added in a second step.

43. Examples

44. Applications Useful in the synthesis of pharmaceuticals, such as converting ketones to secondary alcohols, an important step in the synthesis of many drugs. Applied in the reduction of carboxylic acids to alcohols and esters to primary alcohols. This reaction can create a chiral center from a suitable substrate resulting in formation of a racemic mixture of that compound. For example, when ethyl methyl ketone (butan-2-one) is reduced by metal hydride reduction, a racemic mixture of 2-butanol is produced.

45. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

46. 6. Wolff Kishner reduction

47. The reaction of aldehydes and ketones with hydrazine in basic medium, which reduces the aldehyde or the ketone to a hydrocarbon, is called Wolff- Kishner reduction. The Wolff- Kishner reduction is a chemical reaction used to convert carbonyl compounds (aldehydes or ketones) into their corresponding hydrocarbons (alkanes). Basic Concept: The reaction involves the conversion of the carbonyl group (-C=O) into a methylene group (-CH2-). This reduction occurs under strongly basic conditions and high temperatures The process involves the formation of a hydrazone intermediate followed by its treatment with a strong base, typically hydrazine (N2H4), and heating.

48. General Equation

49. Reaction Mechanism 1) Deprotonation of Nitrogen 2 ) Protonation of the Carbon

50. 3) Deprotonation of Nitrogen 4 ) Protonation of Carbon

51. Applications Conversion of carbonyl compounds (aldehydes or ketones) to corresponding hydrocarbons (aldehydes/ketones are reduced to alkanes). Used in the synthesis of complex organic molecules in pharmaceuticals and agrochemicals. Often employed in the preparation of certain vitamins and hormones. Utilized in the synthesis of aromatic compounds from their corresponding carbonyl compounds. The reaction conditions are relatively mild, making it a versatile tool in organic synthesis.

52. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

53. 7. Friedel Craft’s reaction

54. Aromatic rings will form C-C bonds when treated with alkyl or acyl halides in the presence of a strong Lewis acid (e.g. AlCl 3 ). These are known as  Friedel Crafts  reactions and are examples of  electrophilic aromatic substitution reactions . The Lewis acid coordinates to a lone pair on the halogen, making the halogen a better leaving group. In Friedel -Crafts alkylation, an alkyl halide treated with a Lewis acid results in a carbocation electrophile  (or a species very similar to a carbocation)  that is then attacked by the aromatic ring.  Carbocation rearrangements can occur if they result in a more stable carbocation! Friedel -Crafts acylation is performed with acyl halides and Lewis acids.  No rearrangements  are observed.

55. General Equation

56. Reaction Mechanism Acylation Acylation

57. Examples

58. Applications Used in the petroleum and fragrance industry for the synthesis of alkylated aromatic compounds , which are important in fuels and perfumes. Used to prepare important pharmaceutical compounds like aspirin, ibuprofen, and paracetamol . Helps in the synthesis of antihistamines and antibiotics . Friedel -Crafts alkylation is used in the synthesis of polystyrene, a key polymer in plastics. Many fragrance compounds (e.g., musk ketone) are synthesized using Friedel -Crafts acylation. Many biologically active heterocyclic compounds are prepared using Friedel -Crafts chemistry, such as furan and thiophene derivatives.

59. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

60. 8. Perkin reaction

61. Perkin Reaction is an organic chemical reaction which was discovered by William Henry Perkin, an English chemist. This reaction yields an α, β -unsaturated aromatic acid. Perkin’s reaction mechanism includes the reaction between aromatic aldehydes, the aliphatic acid anhydride, and the alkali salt of the acid to give cinnamic acid derivatives. The Perkin reaction is an organic chemical reaction named after its discoverer – William Henry Perkin .

62. General Equation

63. Reaction Mechanism Step1.  The carboxylate ion abstracts a proton to generate the resonance stabilized carbanion (a species containing carbon with a negative charge). Step2 .  The formation of a tetrahedral intermediate occurs by the nucleophilic addition of the carbanion to the carbonyl carbon of the aldehyde. The acetic acid produced during the reaction protonates the tetrahedral intermediate.

64. Step3.  In this step, the elimination of acetic acid is followed by the hydrolysis of the unsaturated molecule resulting in the production of cinnamic acid.

65. Examples

66. Applications Formation of Furylacrylic acid from Furfural, which provides 65-70% yields. Production of Coumaric acid from the dehydration of salicylaldehyde . Synthesis of phytoestrogenic stilbene resveratrol Cinnamic acid is created in laboratories via Perkin Condensation. Cinnamic acids are unsaturated aromatic carboxylic acids that are present in cinnamon and shea butter. It is utilized to create alpha, and beta-unsaturated aromatic acids, which have a significant impact on the pharmaceutical industry.

67. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

68. 9. Cannizzaro’s reaction

69. The Cannizaro reaction is a chemical reaction in organic chemistry where non enoliazable aldehydes react with a strong base to produce a carboxylic acid and an alcohol. This reaction is a disproportionation reaction, meaning that one molecule of the aldehyde is oxidized to the corresponding carboxylic acid, while another molecule of the aldehyde is simultaneously reduced to the corresponding alcohol. Basic Concept: The Cannizaro reaction proceeds via a nucleophilic addition-elimination mechanism. A strong base, such as hydroxide ion (OH⁻) or an alkoxide ion (RO⁻), attacks the electrophilic carbon of the carbonyl group in the aldehyde, forming a tetrahedral intermediate. The intermediate then undergoes elimination of the alkoxide ion, leading to the formation of the carboxylate anion (salt) and the reduced alcohol. The reaction typically requires the presence of at least one additional equivalent of the aldehyde to ensure that both oxidation and reduction processes occur

70. General Equation

71. Reaction Mechanism Step 1 A nucleophile such as a hydroxide ion is used to attack the carbonyl group of the given aldehyde, causing a disproportionation reaction and giving rise to an anion carrying 2 negative charges.

72. Step 2 This resulting intermediate can now function as a hydride reducing agent. Due to its unstable nature, the intermediate releases a hydride anion. This hydride anion proceeds to attack another aldehyde molecule. Now, the doubly charged anion is converted into a carboxylate anion and the aldehyde is converted into an alkoxide anion

73. Step 3 In this final step, water offers a proton to the alkoxide anion which gives rise to the final alcohol product. The reaction can proceed since the alkoxide is more basic than water. Now, the carboxylate ion gives rise to the final carboxylic acid product when acid workup is used (the acid workup is required since carboxylate is less basic than water and therefore cannot obtain a proton from water).

74. Examples

75. Applications

76. Arndt- Eistert reaction Baeyer- Villiger oxidation Diels Alder reaction Grignard’s reaction Metal Hydride reduction Wolff Kishner reduction Friedel Craft’s reaction Perkin reaction Cannizzaro’s reaction Mannich reaction Introduction General equation Mechanism of action Examples Applications

77. 10. Mannich reaction

78. The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group by formaldehyde and a primary or secondary amine or ammonia. The final product is a β-amino-carbonyl compound also known as a Mannich base . The Mannich reaction is a versatile organic reaction that involves the condensation of a carbonyl compound (typically a ketone or aldehyde), a primary or secondary amine, and a compound containing an acidic proton (such as formaldehyde or its derivatives).

79. The Mannich reaction is an example of nucleophilic addition of an amine to a carbonyl group followed by dehydration to the Schiff base. The Schiff base is an electrophile which reacts in the second step in an electrophilic addition with a compound containing an acidic proton (which is, or had become an enol ). The Mannich reaction is also considered a condensation reaction . In the Mannich reaction, primary or secondary amines or ammonia, are employed for the activation of formaldehyde. Tertiary amines lack an N–H proton to form the intermediate enamine .

80. General Equation

81. Examples

82. Applications The Mannich -Reaction is employed in the organic synthesis of natural compounds such as peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone ). The Mannich reaction is also used in the synthesis of medicinal compounds e.g. rolitetracycline ( Mannich base of tetracycline), fluoxetine (antidepressant), tramadol, and tolmetin (anti-inflammatory drug)and azacyclophanes . The Mannich reaction is employed to synthesize alkyl amines, converting non-polar hydrocarbons into soap or detergents. This is used in a variety of cleaning applications, automotive fuel treatments, and epoxy coatings.