PST05106 Pharmaceutical Organic Chemistry

NTA Level 5 • Semester 1 • PST05106 Structure – Activity Relationship of Cephalosporins Pharmaceutical Organic Chemistry • Source Session/Topic 27 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 27: Structure – Activity Relationship of Cephalosporins. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Cephalosporins • Explain Chemical structure of cephalosporins • Explain the structure – activity relationship of cephalosporins Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Cephalosporins | | | |Presentation | | |3 |40 minutes |Presentation |Chemical Structure of Cephalosporins| |4 |45 minutes | Group |Structure – Activity Relationship of| | | |discussion |Cephalosporins | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes). READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Cephalosporins (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Cephalosporins? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the table below | • Cephalosporins are Antibacterial agents which inhibit bacterial cell wall synthesis. • Cephalosporins are the second group of β-lactam antibiotic family to be discovered after penicillin, which showed broad spectrum of action against Staphylococcus aureus, Vibrio cholerae, and B. anthracis, but moderate antibacterial activity was isolated from the fermentation broth of a strain of A. chrysogenum • Cephalosporins are bactericidal antibiotics, chemically closely related to penicillins, and have the same mode of action, disrupting the synthesis of the peptidoglycan layer of bacterial cell walls of bacteria, causing their death. STEP 3: Chemical Structure of Cephalosporins (40 minutes). • Cephalosporin is a β-lactam antibiotic that inhibits bacterial cell wall synthesis. • In 1948 Dr. Abraham first isolated cephalosporin C from a fungus Cephalosporium acremonium. • Cephalosporins have broader gram –ve coverage than penicillin yet no one of the cephalosporins is active against MRSA and enterococci. Basic structure of cephalosporin is 7-aminocephalosporanic acid [pic] Structural classification of cephalosparins [pic] [pic] STEP 4: Structure – Activity relationship of Cephalosporins (45 minutes). |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small manageable groups. | | | |ASK students to discuss on the following question | |What is the importance of SAR of Cephalosporins? | | | |ALLOW students to discuss for 15 minutes. | | | |ALLOW few groups to present and the rest to add points not mentioned. | | | |CLARIFY and SUMMARIZE by using the contents below | Many analogues of Cephalosporin C have been made and the structure-activity relationship (SAR) conclusions are as follows • The β-lactam ring is essential • A free carboxyl group is needed at position 4. • The bicyclic system is essential • The stereochemistry of the side-groups and the rings is important These are very close to penicillin and there are only a limited number of place where modifications can be made. Those places are: • Variations of the 7-acylamino side chain • Variations of the 3-acetoxymethyl side chain • Extra substitution at carbon 7. [pic] Positions which can be varied Beta-Lactam Ring: • Required for PBP reactivity and antibacterial activity • Reactivity reduced compared to the penicillins • Compare mechanism of action, resistance, pharmacodynamics, etc to penicillins 2-Carboxyl Group: • Acidic: Salt formation, product formulation • Prodrug formation • Elimination profile: Renal X-Substituent: • Cephalosporins and cephamycins • Determines, in part, resistance to beta-lactamase inactivation 3- Substituent (R3) • Chemical/acid stability/instability • Metabolic stability/instability • Minimal impact on antibacterial activity • Protein binding and half-life: Heterocycles • Adverse Reaction and Drug Interaction • Some role in cephalosporin classification (generation) 7-Substituent (R7) • Incorporated by semi synthesis: Variable structures • Impact on spectrum of activity (beta-lactamases, PBP affinity, etc.) • Significant role in activity and classification by generation Cephalosporin analogues [pic] • Different cephalosporins are developed by changing the moieties attached at the 3 and/or 7 positions of the 7-ACA. • Usually, substituents at C-3 (R2) modify the overall pharmacokinetic properties, whereas those at C-7 (R1) alter the antibacterial spectrum. • R1 – the substituents at this position effects β-lactamase resistance and its activity against Gram –ve and/or Gram +ve bacteria (its spectrum). • R2 –these substituents primarily affect the pharmacokinetics: the oral activity, the extent of metabolism, and the duration of action. • Electron withdrawing group at this position provide resonance structure and thus increase stability of the structure. • Carboxylic acid group –necessary for activity, this functional group mimics the carboxylic acid group of alanine when binding the enzyme active site. [pic] STEP 5: Key Points (10 minutes) • The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as "Cephalosporium". • Cephalosporins have broder gram –ve coverage than penicillin yet no one of the cephalosporins is active against MRSA and enterococci. Basic structure of cephalosporin is 7-aminocephalosporanic acid. • Important parameters for the SAR of Cephalosporins which are used to modify its activity includes beta lactam ring, 2-Carboxyl Group, X- Substituent,3- Substituent (R3) and 7- substituent (R7). STEP 6: Evaluation (10 minutes) • What are Cephalosporins? • Draw general chemical structure of cephalosporins. • What is the importance of structure – activity relationship of cephalosporins? References. Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United States: W.B. Saunders Co. Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New

NTA Level 5 • Semester 1 • PST05106 Structure – Activity Relationship of Quinolones Pharmaceutical Organic Chemistry • Source Session/Topic 28 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 28: Structure – Activity Relationship of Quinolones. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Quinolones • Explain Chemical structure of Quinolones • Explain the structure – activity relationship of Quinolones Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Quinolones. | | | |Presentation | | |3 |40 minutes |Presentation |Chemical Structure of | | | | |Quinolones. | |4 |45 minutes | Group |Structure – Activity | | | |discussion |Relationship of Quinolones. | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Quinolones (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Quinolones? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the table below | • The Quinolones (fluoroquinolones) are broad-spectrum antibiotics with particular activity against gram-negative organisms, especially Pseudomonas aeruginosa. • The fluoroquinolones are bactericidal antibiotics that act by specifically targeting DNA gyrase. o Fluoroquinolones can be classified as; o First-generation drugs (e.g., nalidixic acid) o Second-generation quinolones (e.g., ciprofloxacin) o Third-generation drugs (e.g., levofloxacin) o Fourth-generation quinolone drugs (e.g., trovafloxacin) STEP 3: Chemical Structure of Quinolones (40 minutes). The following are chemical structure of quinolones; [pic] STEP 4: Structure – Activity relationship of Quinolones (45 minutes). |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small manageable groups. | | | |ASK students to discuss on the following question | |What is the importance of SAR of fluoroquinolones? | | | |ALLOW students to discuss for 15 minutes. | | | |ALLOW few groups to present and the rest to add points not mentioned. | | | |CLARIFY and SUMMARIZE by using the contents below | [pic] Structure of quinolone • Structure of the quinolone molecule, using the accepted numbering scheme for positions on the molecule. • An R indicates possible sites for structural modification. • Molecules at positions marked by a dashed box can also be changed; however, the most commonly used structure is shown. Position 1. • This position is part of the enzyme-DNA binding complex and has a hydrophobic interaction with the major grove of DNA. • A cyclopropyl substituent is now considered the most potent modification here, followed by addition of a 2,4-difluorophenyl. • Most other substituents, including one with only the wrong stearic position ((R)-ofloxacin) can presumably lower the number of molecules capable of binding to the enzyme-DNA pocket, and therefore reduce potency. • Interestingly, ofloxacin has a tricyclic ring structure with a CH3 attached to the asymmetric C-3 position on the oxazine ring, thus connecting positions 1 and 8 with a fused ring. • Although this has been a useful alternative to the cyclopropyl substituent, the S- isomer exhibits twice the order of magnitude of activity as the R- isomer, which seems to be determined by the number of molecules that can be assembled, or stacked, in the enzyme-DNA complex binding pocket. • Even the potency of the purified S- isomer fused ring is less than that of the cyclopropyl substituent, suggesting the difficulty of improving upon this latter modification. Position 2. • This location is very close to the site for DNA gyrase (or topoisomerase IV) binding so it is believed that any added bulk inhibits access and results in a lower level of microbiological activity. • Only sulfur, incorporated into a small ring, has been able to replace hydrogen at the R-2 position. • To accomplish this, researchers reconfigured positions 3 and 4. Positions 3 and 4. • These two positions on the quinolone nucleus are considered critical for binding to cleaved or perturbed DNA, and no useful substitutions have yet been reported. • Therefore, the 3-carboxylate and 4-carbonyl groups are considered essential for antimicrobial activity. Oxoquinolizines. • This is a new addition to the quinolone class, in which nitrogen replaces the carbon between ring carbons C-4 and C-5. • Making this alteration renumbers the other positions so that 5- becomes 6- , 6- becomes 7-, 7- becomes 8-, and 8- becomes position 9. • This substitution enhances the in vitro and in vivo (mouse protection) activity against gram-positive cocci, including methicillin-resistant S. aureus (MRSA) that are resistant to ciprofloxacin. Position 5. • Substituents at this position of the basic quinolone nucleus appear to have the capacity to alter overall stearic configuration (planar structure) of the molecule, which is how changes here are thought to affect activity. • Modestly sized additions, such as an amino, hydroxyl, or methyl group can markedly increase in vitro activity against gram-positive bacteria, as well as enhance potency against Toxoplasma gondii. • Also, it was found that the methyl group enhances action against gram- positive but not against gram-negative bacteria. Position 6. The addition of a fluorine molecule here markedly improved antimicrobial activity compared to the original quinolone agents and gave rise to the now widely used and clinically successful fluoroquinolone compounds. Position 7. • This position is considered to be one that directly interacts with DNA gyrase, or topoisomerase IV. The optimal substituents at this position have been found to

NTA Level 5 • Semester 1 • PST05106 Structure – Activity Relationship of Sulphonamides Pharmaceutical Organic Chemistry • Source Session/Topic 29 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 29: Structure – Activity Relationship of Sulphonamides. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Sulphonamides • Explain chemical structure of sulphonamides • Explain the structure – activity relationship of sulphonamides Resources Needed: • Flip charts, marker pens, and masking tape • Black/white board and chalk/whiteboard markers SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Sulphonamides. | | | |Presentation | | |3 |40 minutes |Presentation |Chemical Structure of Sulphonamides.| |4 |45 minutes | Group |Structure – Activity Relationship of| | | |discussion |Sulphonamides. | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify. ASK students if they have any questions before continuing. STEP 2: Definition of Sulphonamides (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Sulphonamides? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the table below | Sulphonamides are antibacterial agents which acts against cell metabolism (antimetabolites). Sulfonamides: • Once known as ‘wonder drug’. • Once mainstays of antimicrobial chemotherapy. • The relative cheapness of the sulphonamides is one of their most attractive features and accounts for much of their persistence in the market. STEP 3: Chemical Structure of Sulphonamides (40 minutes). • Sulphonamides are composed of a sulphur atom that has two sets of double bonds to two oxygen atoms, a carbon-based side group, and a nitrogen atom bonded to the sulphur itself. • In organic chemistry, an amide contains a carbonyl group bonded to a nitrogen atom. • Sulphonamides are similar, but the carbonyl group is replaced with sulfone sulphur with two oxygen atoms). • That's why the term 'amide' appears in the name. [pic] General structure of amides and sulphonamides. • The 'R' groups in the figure simply represent any generic carbon-based side chain and could be virtually anything. • For example, R could be a methyl group, a benzene ring, an alkane ring, or some other group. • If the nitrogen atom contains two hydrogens, the sulphonamide is classified primary, if there is one hydrogen it's secondary, and if no hydrogens are present on the nitrogen, it's a tertiary sulphonamide [pic] Structures of primary, secondary, and tertiary sulphonamides. Important Sulfonamide Derivatives • Sulfamethoxazole • Sulfamethoxazole is another sulfonamide with antibacterial activity and is commonly used in the treatment of urinary tract infections and bronchitis. • Sulfamethoxazole looks very similar to sulfanilamide in terms of its structure but contains an extra ring system called an oxazole. [pic] STEP 4: Structure – Activity Relationship of Sulphonamides (45 minutes). |Activity: Small Group Discussion (20 minutes). | | | |DIVIDE students into small manageable groups. | | | |ASK students to discuss on the following question. | |What is the importance of SAR of sulphonamides? | | | |ALLOW students to discuss for 15 minutes. | | | |ALLOW few groups to present and the rest to add points not mentioned. | | | |CLARIFY and SUMMARIZE by using the contents below | The synthesis of a large number of sulphonamide analogues led to the following conclusions [pic] Sulfonamides analogues • The para -amino group is essential for activity and must be unsubstituted (i.e. R1=H). The only exception is when R1=acyl (i.e. amides). • The amides themselves are inactive but can be metabolized in the body to regenerate the active compound. • Thus, amides can be used as sulfonamide prodrugs. • Incorporation of other groups (halogen, alkyl, etc.) destroys the activity. [pic] Metabolism of acyl group to regenerate active compound • The aromatic ring and the sulphonamide functional group are both required. • Total loss of antibacterial activity occurs if sulphonamide group is replaced by other acidic groups (sulfonic, phosphoric etc.) • The aromatic ring must be para -substituted only. • Extra substitution eliminates activity for steric reasons. • The sulfonamide nitrogen must be primary (sulfanilamide) or secondary (acidic proton is essential for antibacterial activity). • R2 is the only possible site that can be varied in sulfonamides. Sulphonamide analogues • R2 can be varied by incorporating a large range of heterocyclic or aromatic structures, which affects the extent to which the drug binds to plasma protein. • This in turn controls the blood levels of the drug such that it can be short acting or long acting. • Thus, a drug which binds strongly to plasma protein will be slowly released into the blood circulation and will be longer lasting. • R2 affects pharmacokinetic properties but not the pharmacodynamics properties. Sulfonamide analogues with reduced toxicity • Changing the nature of the group R2 has also helped to reduce the toxicity of some sulfonamides. • The primary amino groups of sulfonamides are acetylated in the body and the resulting amides have reduced solubility which can lead to toxic effects. • For example, the metabolite formed from sulfathiazole is poorly soluble and can prove fatal if it blocks the kidney tubules [pic] Insoluble • It was discovered that the solubility problem could be overcome by replacing the thiazole ring in sulfathiazole with a pyrimidine ring to give sulfadiazine. [pic] • Its metabolites will also be water soluble • The reason for the improved solubility lies in the acidity of the sulphonamide NH proton. • In sulfathiazole, this proton

NTA Level 5 • Semester 1 • PST05106 Structure – Activity Relationship of Aspirin Pharmaceutical Organic Chemistry • Source Session/Topic 30 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 30: Structure – Activity Relationship of Aspirin. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Aspirin • Explain Chemical structure of aspirin • Explain the structure – activity relationship of aspirin Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Aspirin | | | |Presentation | | |3 |40 minutes |Presentation |Chemical Structure of Aspirin | |4 |45 minutes |Group |Structure – Activity Relationship of| | | |discussion |Aspirin | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify. ASK students if they have any questions before continuing. STEP 2: Definition of Aspirin (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What is Aspirin? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the table below | • Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) effective in treating fever, pain, and inflammation in the body. • It also prevents blood clots (i.e., is antithrombotic). As a group, NSAIDs are non-narcotic relievers of mild to moderate pain of many causes, including o Headaches, o Injury, o Menstrual cramps, o Arthritis, and other musculoskeletal conditions • Other members of this class include o ibuprofen (Motrin), o indomethacin (Indocin), o nabumetone (Relafen) and several others. • They all work by reducing the levels of prostaglandins, chemicals that are released when there is inflammation and that cause pain and fever. • NSAIDs block the enzyme that makes prostaglandins (cyclooxygenase), resulting in lower concentrations of prostaglandins. • As a consequence, inflammation, pain, and fever are reduced. • Inhibition of prostaglandins also reduces the function of platelets and the ability of blood to clot. STEP 3: Chemical Structure of Aspirin (40 minutes). • Acetylsalicylic acid –or, as it is more commonly known, aspirin –has a simple chemical structure. • It consists of a small number of carbons, hydrogen and oxygen atoms that form the chemical bonding patterns shown below. • Aspirin Acetylsalicylic acid C9H8O4 [pic] • One of the best-known aromatic acetates is acetylsalicylic acid, or aspirin, which is prepared by the esterification of the phenolic hydroxyl group of salicylic acid. [pic] • Aspirin possesses a number of properties that make it the most often recommended drug which are; o analgesia, leading to pain relief o anti-inflammatory effect, providing some relief from the swelling associated with arthritis and minor injuries. o antipyretic effect, which means it reduces fever. Synthesis • The key compound in the synthesis of aspirin, salicylic acid, is prepared from phenol by Kolbe synthesis (also known as the Kolbe- Schmitt reaction) whereby sodium phenoxide is heated with CO2 under pressure and the reaction mixture is subsequently acidified to yield salicylic acid. [pic] STEP 4: Structure – Activity relationship of Aspirin (45 minutes). |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small manageable groups. | | | |ASK students to discuss on the following question | |What is the importance of SAR of aspirin? | | | |ALLOW students to discuss for 15 minutes. | | | |ALLOW few groups to present and the rest to add points not mentioned. | | | |CLARIFY and SUMMARIZE by using the contents below | • Despite the vast effort that has been expended in the search to find a “better” aspirin—that is, one possessing fewer GI side effects, but a greater potency and a longer duration of action yet is inexpensive and an antipyretic, analgetic, and anti-inflammatory agent that is overall superior to aspirin—none has yet to be discovered. The following structure–activity relationships have been established: [pic] • Possesses a free carboxylic acid (COOH) for an ionic interaction with the positively charged arginine residue at the active site of the cyclooxygenases (i.e., Arg-120 in COX-1 or Arg-106 in COX-2 isozymes). • This acidic moiety is further linked to an aromatic (or heteroaromatic) ring for binding to either the Δ5-double-bond or Δ8- double-bond binding regions. • The active moiety appears to the salicylate anion. • The side effects of aspirin, particularly the GI effects, appear to be associated with the carboxylic acid function. • Reducing the acidity of this group (e.g., converting to an amide, salicylamide) maintains the analgesic actions of salicylic acid derivatives but eliminates the anti-inflammatory properties. • Substitution on either the carboxyl or phenolic hydroxyl groups may affect potency and toxicity. • Benzoic acid itself has only weak anti-inflammatory activity. • Placing the phenolic hydroxyl group meta or para to the carboxyl group abolishes this activity. • Substitution of halogen atoms on the aromatic ring enhances potency and toxicity. • Substitution of aromatic rings at the 5-position of salicylic acid increases anti-inflammatory activity (e.g., diflunisal). STEP 5: Key Points (10 minutes). • Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) effective in treating fever, pain, and inflammation in the body. • Aspirin possesses a free carboxylic acid (COOH) for an ionic interaction with the positively charged arginine residue at the active site of the cyclooxygenases. • Modification of carboxylic acid function group of aspirin may help in reducing its GI toxicity. STEP 6: Evaluation (10 minutes). • What is Aspirin? • Draw chemical structure of aspirin. • What

NTA Level 5 • Semester 1 • PST05106 Structure – Activity Relationship of Paracetamol Pharmaceutical Organic Chemistry • Source Session/Topic 31 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 31: Structure – Activity Relationship of Paracetamol. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Paracetamol • Explain Chemical structure of paracetamol • Explain the structure – activity relationship of paracetamol Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Paracetamol | | | |Presentation | | |3 |40 minutes |Presentation |Chemical Structure of Paracetamol | |4 |45 minutes |Group |Structure – Activity Relationship of| | | |discussion |Paracetamol | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes). READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Paracetamol (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What is paracetamol? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the table below | • Paracetamol also known as acetaminophen is an analgesic antipyretic derivative of acetanilide. • Acetaminophen has weak anti-inflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. • Acetaminophen is a p-aminophenol derivative with analgesic and antipyretic activities. • Although the exact mechanism through which acetaminophen exert its effects has yet to be fully determined, acetaminophen may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate (NMDA) and substance P, resulting in elevation of the pain threshold. • The antipyretic activity may result from inhibition of prostaglandin synthesis and release in the central nervous system (CNS) and prostaglandin-mediated effects on the heat-regulating center in the anterior hypothalamus. • Acetaminophen is a widely used nonprescription analgesic and antipyretic medication for mild-to-moderate pain and fever. • Harmless at low doses, acetaminophen has direct hepatotoxic potential when taken as an overdose and can cause acute liver injury and death from acute liver failure. • Even in therapeutic doses, acetaminophen can cause transient serum aminotransferase elevations. Summary • Paracetamol (acetaminophen) is a pain reliever and a fever reducer. • Paracetamol is used to treat many conditions such as headache, muscle aches, arthritis, backache, toothaches, colds, and fevers. It relieves pain in mild arthritis but has no effect on the underlying inflammation and swelling of the joint. STEP 3: Chemical Structure of Paracetamol (40 minutes). • The acetaminophen has the IUPAC name N-(4-hydroxyphenyl) acetamide and its chemical formula us C8H9NO2 and its extended formula is HOC6H4NHCOCH3. • Its molar mass is 151.165 g mol-1. • The molecule is formed by an aromatic phenyl ring, which has two substituents in position -para (1,4). • The first substituent is an amide group (acetamide) and the second is a hydroxy group (-OH). • The molecule is planar with 7 carbon atoms with sp2 hybridization. • Its chemical structure can be written as below, in the common representations used for organic molecules. [pic] STEP 4: Structure – Activity relationship of Paracetamol (45 minutes) |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small manageable groups | | | |ASK students to discuss on the following question. | |What is the importance of SAR of paracetamol? | | | | | |ALLOW students to discuss for 15 minutes. | | | |ALLOW few groups to present for 5 minutes and the rest to add points | |not mentioned. | | | |CLARIFY and SUMMARIZE by using the contents below | • Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern. • The amide group is acetamide (ethanamide). • It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen is all conjugated. • The presence of two activating groups also makes the benzene ring highly reactive toward electrophilic aromatic substitution. • As the substituents are ortho,para-directing and para with respect to each other, all positions on the ring are more or less equally activated. • The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion. • Structure and reactivity of acetaminophen accounts for its chemical properties • Based on the comparative toxicity of acetanilide and acetaminophen, aminophenols are less toxic than the corresponding aniline derivatives, although p-aminophenol itself is too toxic for therapeutic purposes. • Etherification of the phenolic function with methyl or propyl groups produces derivatives with greater side effects than with ethyl groups. Substituent • The nitrogen atoms that reduce basicity reduce activity unless that substituent is metabolically labile (e.g., acetyl). • Amides derived from aromatic acids (e.g., N-phenylbenzamide) are less active or inactive. • As indicated, both acetanilide and phenacetin are metabolized to acetaminophen. Additionally, both undergo hydrolysis to yield Aniline derivatives that produce directly, or through their conversion to hydroxylamine derivatives, significant methemoglobinemia and hemolytic anemia, which resulted in their removal from the U.S. market. STEP 5: Key Points (10 minutes) • Paracetamol also known as acetaminophen is an analgesic antipyretic derivative of acetanilide • The SAR of paracetamol may

NTA Level 5 • Semester 1 • PST05106 Biotransformation of Medicinal Products Pharmaceutical Organic Chemistry • Source Session/Topic 32 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 32: Biotransformation of Medicinal Products. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define biotransformation • Explain metabolism of different organic compounds • Explain the importance of biotransformation Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Biotransformation | | | |Presentation | | |3 |60 minutes |Presentation |Metabolism of Organic Compounds | |4 |25 minutes |Group |Importance of Biotransformation | | | |discussion | | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Biotransformation (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What is Biotransformation? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the table below | • Biotransformation is Chemical alteration of the drug in body that converts non-polar or lipid soluble compounds to polar or lipid insoluble compounds. OR • Biochemical alteration of chemicals such as (but not limited to) nutrients, amino acids, toxins, and drugs in the body. • It is also needed to render non-polar compounds polar so that they are not reabsorbed in renal tubules and are excreted. • The body typically deals with a foreign compound (DRUGS) by making it more water-soluble, to increase the rate of its excretion through the urine. STEP 3: Metabolism of Organic Compounds (60 minutes). • Termination of drug effect is by the process of drug elimination which involves mainly 2 processes: one of them is drug metabolism. • Metabolism is predominantly done in the liver due to its richness in enzymes • The enzymes that are responsible for drug metabolism in the liver are; o Microsomal mixed function oxidases (MFOs) system involved. o Cytochrome P450 enzymes play important role. • Other organs responsible for drug metabolism are; o Lungs o Kidney o Intestine o Placenta o Skin o Brain o Testes o Muscle o Spleen • Metabolism of drugs makes them: o More polar o Ionizable o Water soluble to enhance renal excretion o More active (for pro drugs) Drug Metabolism in the Liver • There are two phases of drug metabolism in the liver. • Phase I reaction • Phase II reaction PHASE I REACTIONS • A polar group is introduced/ unmasked to make the drug molecule more water-soluble & less active to be excreted. • Reactions are non-synthetic in nature. • The majority of metabolites are generated by a common hydroxylating enzyme system known as Cytochrome P450. o Oxidation o Reduction o Hydrolytic cleavage o Dealkylation o Ring cyclization o N-carboxylation o Dimerization o Transamidation o Isomerization o Decarboxylation • Oxidation of aromatic carbon atoms (aromatic hydroxylation): [pic] • Oxidation of olefins (C=C bonds): o Oxidation of non-aromatic C=C bonds is analogous to aromatic hydroxylation. i.e. it proceeds via formation of epoxides to yield 1,2- dihydrodiols [pic] • Oxidation of Benzylic Carbon Atoms o Carbon atoms attached directly to the aromatic ring are hydroxylated. [pic] • Oxidation of Allylic carbon Atoms o Carbon atoms adjacent to Olefinic double bonds (are allylic carbon atoms) also undergo hydroxylation in a manner similar to Benzylic Carbons. [pic] • Oxidation of Carbon Atoms Alpha to Carbonyls and Imines o Several Benzodiazepines contain a carbon atom (C-3) alpha to both Carbonyl (C=0) and imino (C=N) function which readily undergoes Hydroxylation. [pic] • Oxidation of Aliphatic Carbon Atoms (Aliphatic Hydroxylation) o Terminal hydroxylation of methyl group yields primary alcohols which undergoes further oxidation to aldehydes and then to carboxylic acid. [pic] • Oxidation of Alicyclic Carbon Atoms (Alicyclic Hydroxylation) o Cyclohexane (alicyclic) and piperidine (non-aromatic heterocyclic) rings are commonly found in a number of molecules. o Such rings are generally hydroxylated at C-3 or C-4 positions. [pic] • Oxidation Of Carbon-Heteroatom Systems o Biotransformation of C-N, C-0 & C-S system proceed in one of the two ways: ▪ Hydroxylation of carbon atom attached to the heteroatom and subsequent cleavage at carbon-heteroatom bond. E.g. N-, O- & S- dealkylation, oxidative deamination & desulfuration. ▪ Oxidation of the heteroatom itself. E.g. N- & S- oxidation. • Oxidation of Carbon-Nitrogen System o N-DEALKYLATION: ▪ Mechanism of N-dealkylation involve oxidation of α-carbon to generate an intermediate carbinolamine which rearranges by cleavage of C-N bond to yield the N dealkylated product and the corresponding carbonyl of the alkyl group. [pic] ▪ A tertiary nitrogen attached to different alkyl groups undergoes dealkylation by removal of smaller alkyl group first. Example: o 2º aliphatic amine e.g. Methamphetamine. o 3º aliphatic amine e.g. imipramine o 3º alicyclic amine e.g. hexobarbital o Amides e.g. Diazepam o N-HYDROXYLATION: ▪ Converse to basic compounds that form N-oxide, N- hydroxy formation is usually displayed by non-basic nitrogen atoms such as amide Nitrogen. [pic] • Oxidation of Carbon-Sulfur Systems o S-DEALKYLATION: ▪ The mechanism of S-Dealkylation of thioethers is analogous to N- dealkylation .IT proceed via α-carbon hydroxylation. ▪ The C-S bond cleavage results in formation of a thiol and a carbonyl product. [pic] • Desulfuration: o This reaction also involves cleavage of carbon-sulfur bond (C=S). o The product is the one with C=0 bond. o Such a desulfuration reaction is commonly observed in thioamides such as thiopental [pic]

NTA Level 5 • Semester 1 • PST05106 Pharmaceutical Organic Chemistry – Complete Full Notes Complete educational source text in one page Completeness safeguard: this page keeps the complete educational module/source wording in one place so learning material is not lost when browsing topic by topic. Presenter/tutor metadata is intentionally excluded. UNITED REPUBLIC OF TANZANIA [pic] Ministry of Health, Community Development, Gender, Elderly and Children Facilitator Guide Copyright © Ministry of Health, Community Development, Gender, Elderly and Children – 2018 Table of Contents Table of Contents iii Background iv Acknowledgment v Introduction vii Abbreviations/Acronym xi Session 1: Introduction to Pharmaceutical Organic Chemistry. 1 Session 2: Classification of Organic Compounds. 8 Session 3: Classification of Drugs According to Their Chemical Nature. 14 Session 4: Nomenclature of Organic Compounds. 17 Session 5: General Properties of Organic Compounds. 23 Session 6: Chemical Reaction in Organic Compounds. 32 Session 7: Isomerism. 38 Session 8: Alkanes of Pharmaceutical Importance. 48 Session 9: Alkenes of Pharmaceutical Importance. 57 Session 10: Alkynes of Pharmaceutical Importance. 73 Session 11: Alcohols of Pharmaceutical Importance. 84 Session 12: Carboxylic Acids of Pharmaceutical Importance. 101 Session 13: Esters of Pharmaceutical Importance. 114 Session 14: Acyl Chlorides of Pharmaceutical Importance. 122 Session 15: Ethers of Pharmaceutical importance. 128 Session 16: Aldehydes of Pharmaceutical Importance. 138 Session 17: Ketones of Pharmaceutical Importance. 148 Session 18: Aromatic Organic Compounds of Pharmaceutical Importance . 161 Session 19: Phenols of Pharmaceutical Importance. 175 Session 20: Aryl Halides of Pharmaceutical Importance. 188 Session 21: Amines of Pharmaceutical Importance. 200 Session 22: Amides of Pharmaceutical Importance. 216 Session 23: Introduction to Heterocyclic Compounds. 224 Session 24: Chemical Reactions of Heterocyclic Compounds. 234 Session 25: Introduction to Structure – Activity Relationship of Drugs. 243 Session 26: Structure – Activity Relationship of Penicillins. 247 Session 27: Structure – Activity Relationship of Cephalosporins. 257 Session 28: Structure – Activity Relationship of Quinolones. 264 Session 29: Structure – Activity Relationship of Sulphonamides. 271 Session 30: Structure – Activity Relationship of Aspirin. 279 Session 31: Structure – Activity Relationship of Paracetamol. 285 Session 32: Biotransformation of Medicinal Products. 290 Background There is currently an ever-increasing demand for pharmaceutical personnel in Tanzania. This is due to expanding investment in public and private pharmaceutical sector. Shortage of trained pharmaceutical human resource contributes to poor quality of pharmaceutical services and low access to medicines in the country (GIZ, 2012). Through Public-Private-Partnership (PPP) the Pharmacy Council (PC) together with Development Partners (DPs) in Germany and Pharmaceutical Training Institutions (PTIs) worked together to address the shortage of human resource for pharmacy by designing a project named “Supporting Training Institutions for Improved Pharmaceutical Services in Tanzania” in order to improve quality and capacity of PTIs in training, particularly of lower cadre pharmaceutical personnel. The Pharmacy Council formed a Steering committee that conducted a stakeholder’s workshop from18th – 22ndAugust 2014 in Morogoro to initiate the implementation of the project. Key activities in the implementation of this project included carrying out situational analysis, curriculum review and harmonization, development of training manual/facilitators guide, development of assessment plan, training of trainers and supportive supervision. After the curricula were reviewed and harmonized, the process of developing standardised training materials started through Writer’s Workshop approach. The approach included a number of workshops for developing, reviewing, editing and formatting the sessions of the modules. The goals of writer’s workshops were to build capacity of tutors in the development of training materials and to develop high-quality, standardized teaching materials. The training package for pharmacy cadres includes a facilitator guide, assessment plan and practicum. There are 11 modules for NTA level 5 making 11 facilitator guides including one practicum guide. Acknowledgment The development of standardized training materials of a competence-based curriculum for pharmaceutical sciences has been accomplished through involvement of different stakeholders. Special thanks go to the Pharmacy Council for spearheading the harmonization of training materials in the pharmacy after noticing that training institutions in Tanzania were using different curricula and train their students differently. I would also like to extend my gratitude to Christian Social Service Commission (CSSC) for their tireless efforts to mobilize funds from development partners. Special thanks to Multi Actors Partnership (MAP) for the financial and technical support. Particular thanks are due to those who led this important process to its completion, Centre for Education Development in Health Arusha (CEDHA), Ms. Diana Gamuya, Mr. Dickson Mtalitinya and Members from the secretariat of National Council for Technical Education (NACTE) for facilitating the process. Finally, I very much appreciate the contributions of the tutors and content experts representing PTIs, hospitals, and other health training institutions. Their participation in meetings and workshops, and their input in the development of this training manual/facilitators guide have been invaluable. These participants are listed with our gratitude below: Ms. Elizabeth Shekalaghe Registrar, Pharmacy Council of Tanzania Dr. Catherine Jincen Principal, CEDHA Dr. Saitore Laizer Deputy Principal, CEDHA Dr. Sungwa N. Kabissi Project Manager – MAP, CSSC Ms. Diana Gamuya CEDHA Ms. Emily Mwakibolwa Pharmacy Council Ms. Tumaini H. Lyombe MUHAS Ms. Dilisi J. Makawia KSP Director of Human Resources Development Ministry of Health, Community Development, Gender, Elderly and Children Introduction Module Overview This module content is a guide for tutors of Pharmaceutical schools for training of students. The session contents are based on sub-enabling outcomes and their related tasks of the curriculum for Basic Technician Course in Pharmaceutical Sciences. The module sub-enabling outcomes and their related tasks are as indicated in the Ordinary Technician Certificate in Pharmaceutical Sciences (NTA Level 5) Curriculum. Target Audience This module is intended for use primarily by tutors of pharmaceutical schools. The module’s sessions give guidance on the time, activities and provide information on how to teach the session. The sessions include different activities which focus on increasing students’ knowledge, skills and attitudes. Organization of the Module The module consists of thirty-two (32) sessions; each session is divided into several parts as indicated below: • Session Title: The name of the session • Total Session Time: The estimated time for teaching the session, indicated in

NTA Level 5 • Semester 1 • PST05106 Introduction to Pharmaceutical Organic Chemistry Pharmaceutical Organic Chemistry • Source Session/Topic 1 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 1: Introduction to Pharmaceutical Organic Chemistry. Total Session Time: 120 minutes Prerequisites: PST 04210 Inorganic Chemistry Learning Tasks By the end of this session students are expected to be able to: • Define pharmaceutical organic chemistry • List characteristics of organic compounds • Explain the importance of organic chemistry in pharmacy Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW. |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |15 minutes |Buzzing. |Definition of Pharmaceutical Organic| | | |Presentation. |Chemistry. | |3 | |Brainstorming.| | | |35 minutes |Presentation. |Characteristics of Organic | | | | |Compounds. | |4 |45 minutes |Group |Importance of Organic Chemistry in | | | |discussion. |Pharmacy. | | | |Presentation. | | |5 |10minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENT. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify. ASK students if they have any questions before continuing. STEP 2: Definition of Pharmaceutical Organic Chemistry (15 minutes) |Activity: Buzzing (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What is a pharmaceutical Organic Chemistry? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the content below. | • Organic Chemistry is the branch of Chemistry which deals with the study of carbon and its compounds. o However, carbon monoxide, carbon dioxide, carbonates, hydrogen carbonates, carbides and cyanides are excluded. • Pharmaceutical Organic Chemistry is the study of all substances containing carbon which are involved with design, chemical synthesis and development of bioactive molecules (drugs). • Two aspects are involved o Medicinal Chemistry – which is devoted to discovery and development of new agents for treating diseases. o Biochemistry – study of the cell & analysis of its structure to identify factors necessary for life of every cell. • Occurrence of Carbon and Sources of Organic Compounds. o Carbon is the principle element in organic compounds; most also contain hydrogen and others contain the halogens, nitrogen, oxygen, phosphorus, sulphur etc. o Occurs widely in carbohydrates, proteins, fats, vitamins, nucleic acids, hormones and synthetic materials such as drugs, ink and dyes. o Major sources are petroleum, coal and natural gases. o Other sources include wood, oils and agricultural waste products o Biggest source of organic compounds – plants & animals • The Unique Nature of Carbon o Ability to catenate ▪ Carbon atoms link together to form chains of varying length, branched chains and rings of different sizes o Ability to form four strong single covalent bonds (tetravalency) ▪ Each carbon atom has four unpaired electrons when excited, as a 4A element in the periodic table, it can share 4 valence electrons – tetravalent, Tend to form four strong covalent bonds o Ability to Form Multiple Bonds ▪ Carbon atom has the ability to form the multiple bonds links with itself. ▪ There two categories of multiple bond (i) double bonds eg C=C (ii) triple bonds eg C≡C. ▪ The compounds formed in this way have different properties from compounds of the same elements but single bond. o Carbon atom can vary in oxidation state from -4 to +4 CH4 Carbon oxidation number -4 CCl4 Carbon oxidation number +4 STEP 3: Characteristics of Organic Compounds (35 minutes). |Activity: Brainstorming (10minutes) | | | |ASK students to pair up and buzz on the following question for 5 | |minutes | | | |What are the characteristics of organic compounds? | | | |ALLOW pairs to respond on the question | | | |WRITE their response on the flip chart/board | | | |CLARIFY and SUMMARIZE by using the content in the table 1 below | The following are the characteristics of organic compounds • Covalent nature o Carbon atom from strong covalent bonds with one another, most organic compounds are stable because of the strong carbon -carbon bonds, since they have a covalent nature they do not ionizes in solution and are non-conductors of electricity. • Polarity and solubility of non-polar compounds o Carbon-hydrogen bonds are non-polar like carbon-carbon bonds; this is because of the almost equal electro negativities of the two elements. o Most of the organic compounds are non-polar unless the compounds consist of very electronegative elements like chlorine or groups like the hydroxyl group, they cannot therefore form bonds with water molecules (insoluble in water). o If an organic compound contain polar groups hydrogen bond can form between polar group in the molecule of organic compound and the water molecule. o For the example ethanol molecule contains a hydroxyl group which is polar, so it is soluble in water. • Low melting and boiling points o Organic compounds generally have low melting and boiling points than inorganic compounds; this is because these compounds possess relatively weak intermolecular bonds which can easily broke by heat energy. • Thermal instability o Many organic compounds are; thermally unstable, decomposing into simpler molecules when heated to temperature above 5000C. o However, this property is sometimes of commercial importance as in the cracking of petroleum. o This property is very useful in the fractional distillation of crude oils. • Flammability o Most organic compounds are flammable (catch fire easily) and burn exothermically in a plentiful supply of air to yield carbon (IV) oxide and water. o Thus, most fuels such as woods, coal, oil, petrol and natural gas are organic, and their combustion provides our main source of heat energy. • Reactivity o Reactions involving organic

NTA Level 5 • Semester 1 • PST05106 Aldehydes of Pharmaceutical Importance Pharmaceutical Organic Chemistry • Source Session/Topic 16 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 16: Aldehydes of Pharmaceutical Importance. Total Session Time: 120 minutes Prerequisites • None Learning Tasks By the end of this session students are expected to be able to: • Define aldehydes • List aldehydes and their isomers • Explain nomenclature of aldehydes • Draw chemical structure of aldehydes • List chemical properties of aldehydes • Explain chemical reactions of aldehydes Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Aldehydes | | | |Presentation | | |3 |10 minutes |Presentation |Aldehydes and their Isomers | |4 |15 minutes |Presentation |Nomenclature of Aldehydes | |5 |15 minutes |Presentation |Chemical Structure of Aldehydes | |6 |15 minutes |Buzzing |Chemical Properties of Aldehydes | | | |Presentation | | |7 |35 minutes |Group |Chemical Reactions involving | | | |discussion |Aldehydes | | | |Presentation | | |8 |05 minutes |Presentation |Key Points | |9 |05 minutes |Presentation |Evaluation | SESSION CONTENTS. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes). READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Aldehydes (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Aldehydes? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the content below | Aldehydes are compounds of the general formula RCHO (R may be aliphatic or aromatic group) Examples of aldehydes In aldehydes, the carbonyl group has a hydrogen atom attached to it together with either • a second hydrogen atom Or • More commonly, a hydrocarbon group which might be an alkyl group or one containing a benzene ring. [pic] ALDEHYDE STEP 3: Aldehydes and their Isomers (10 minutes). Aldehydes exhibit the following type of isomerism: • Chain (nuclear) Isomerism. o Aldehydes with 4 or more carbon atoms show chain isomerism. For example: [pic] • Position isomerism. o Aromatic aldehydes and higher ketones give position isomers. For example: [pic] • Functional Isomerism. o The general formula of aldehydes, ketones, unsaturated alcohols oxiranes and oxolanes is CnH2nO o C3H6O has isomers as: [pic] STEP 4: Nomenclature of Aldehydes (15 minutes). I. The longest chain carrying the –CHO group is considered as the parent structure. Aldehydes are named by replacing the ‘-e’ of the corresponding alkane by the ending ‘-al’ [pic] II. When R is aromatic just the word aldehyde is added to the aromatic name III.The common name of simple aldehydes end with ‘aldehyde’ Examples: Formaldehyde (=methanal) Acetaldehyde (=ethanal) Propionoaldehyde (=propanal) Butyraldehyde (=butanal) IV. If the aldehyde group is attached to a large unit (ring), the suffix carbaldehyde is used.[pic] [pic] STEP 5: Chemical Structure of Aldehydes (15 minutes). In an aldehyde, at least one of the attached groups must be a hydrogen atom. The following compounds are aldehydes: [pic] • In condensed formulas, we use CHO to identify an aldehyde rather than COH, which might be confused with an alcohol. • This follows the general rule that in condensed structural formulas H comes after the atom it is attached to (usually C, N, or O). [pic] Some structures of simple aldehydes [pic] STEP 6: Chemical Properties of Aldehydes (15 minutes). |Activity: Buzzing (5minutes) | | | |ASK students to pair up and buzz on the following question for 5 | |minutes. | | | |What are the chemical properties of Aldehydes? | | | |ALLOW pairs to respond on the question. | | | |WRITE their response on the flip chart/board. | | | |CLARIFY and SUMMARIZE by using the content in the table 1 below | • Aldehydes can be reduced to a variety of compounds under different conditions with different reducing agents. • Aldehydes are reduced to the corresponding alcohols by; o Addition of hydrogen in the presence of catalysts like finely divided platinum, palladium, nickel and ruthenium. o Treatment with chemical reagents such as sodium borohydride (NaBH4) or Lithium aluminium hydride (LiAlH4). • Aldehydes are easily oxdised to carboxylic acids on treatment with common oxidising agents like nitric acid, potassium permanganate, potassium dichromate etc. • Aldehydes respond to the Fehlings' test. o Fehlings' solution is an alkaline solution of copper sulphate containing sodium potassium tartrate (Rochelle Salt) as a complexing agent. o Aldehydes on warming with solution, give a red precipitate of cuprous oxide as a result of the redox reaction. o Aromatic aldehydes give very poor results in this test. STEP 7: Chemical Reactions involving Aldehydes (35 Minutes). |Activity: Small Group Discussion (15 minutes) | | | |DIVIDE students into small groups. | | | |ASK students to discuss in groups on the following questions | |What are the chemical reactions involving Aldehydes? | | | |[pic]REFER Students to Book | | | |ALLOW students to discuss for 10 minutes. | | | |ALLOW each group to present for 5 minutes. | | | |CLARIFY and SUMMARIZE by using the contents below | • Aldehydes undergo many reactions to give a wide variety of useful derivatives. • Their most common reaction is nucleophilic addition, addition of a nucleophile and a proton across the C = O double bond. • The reactivity of the carbonyl group arises from the electronegativity of the oxygen atom and the resulting polarization of the carbon-oxygen double bond. • The electrophilic carbonyl carbon atom is sp2 hybridized and flat, leaving it relatively unhindered and open to attack from either face of the double bond.

NTA Level 5 • Semester 1 • PST05106 Ethers of Pharmaceutical importance Pharmaceutical Organic Chemistry • Source Session/Topic 15 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 15: Ethers of Pharmaceutical importance. Total Session Time: 120 minutes Prerequisites • None Learning Tasks By the end of this session students are expected to be able to: • Define ethers • List ethers and their isomers • Explain nomenclature of ethers • Draw chemical structure of ethers • List chemical properties of ethers • Explain chemical reactions of ethers Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Ethers | | | |Presentation | | |3 |10 minutes |Presentation |Ethers and their Isomers | |4 |15 minutes |Presentation |Nomenclature of Ethers | |5 |15 minutes |Presentation |Chemical Structure of Ethers | |6 |15 minutes |Buzzing |Chemical Properties of Ethers | | | |Presentation | | |7 |35 minutes |Group |Chemical Reactions involving Ethers | | | |discussion | | | | |Presentation | | |8 |05 minutes |Presentation |Key Points | |9 |05 minutes |Presentation |Evaluation | SESSION CONTENTS. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Ethers (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Ethers? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the content below | • Ethers are compounds of formula R – 0 – R ', where R and R' may be alkyl groups or aryl (benzene ring) groups. • Ethers can be considered derivatives of water (HOH) or alcohols (ROH) by replacing an H with an R group. • In an alcohol, one hydrogen atom of water is replaced by an alkyl group. • In an ether, both hydrogens are replaced by alkyl groups. [pic] • The R groups in ethers can be alkyl, aryl, or alkenyl. • The R groups can be the same or different. • If the R groups are the same, the ethers are called symmetrical ethers. • If the R groups are different, the ethers are called unsymmetrical ethers. • Ethers can be cyclic or acyclic. • Rings that contain an atom other than carbon are called heterocyclic compounds. • Oxygen is the heteroatom in cyclic ethers. Examples of ethers [pic] • The most important commercial ether is diethyl ether, often called "ethyl ether’’, or simply "ether." STEP 3: Ethers and their Isomers (10 minutes). Aliphatic Ethers can give two different types of isomers. • Chain isomerism o Ethers with the same formula and having different carbon chain skeletons are called chain isomers. o Examples: [pic] • Functional isomers. o Ethers are isomeric with alcohols. o Example: [pic] is isomeric with ethyl alcohol C2H5OH • Metamerism o Isomers with the same molecular formula but different alkyl groups (around the functional group) are called metamers. An ether with formula C4H10O has 3 metamers. [pic] STEP 4: Nomenclature of Ethers (15 minutes). • The IUPAC system, generally used with more complicated ethers, is sometimes called the alkoxy alkane system. • The common nomenclature of ethers, which is sometimes called the alkyl alkyl ether system has also been widely used • IUPAC names use the more complex alkyl group as the root name, and the rest of the ether as an alkoxy group. • For example, cyclohexyl methyl ether is named methoxycyclohexane. • This systematic nomenclature is often the only clear way to name complex ethers. Example, [pic] [pic] |Table 1: Common Alkyl and Alkoxy Groups | |Alkyl Group |Name | |Alkoxy Group |Name | |CH3– |Methyl | |CH3O– |Methoxy | |CH3CH2– |Ethyl | |CH3CH2O– |Ethoxy | |(CH3)2CH– |Isopropyl | |(CH3)2CHO– |Isopropoxy | |(CH3)3C– |tert-Butyl | |(CH3)3CO– |tert-Butoxy | |C6H5– |Phenyl | |C6H5O– |Phenoxy | Common Names (Alkyl Alkyl Ether Names) • Common names of ethers are formed by naming the two alkyl groups on oxygen and adding the word ether. • Under the current system, the alkyl groups should be named in alphabetical order, but many people still use the old system, which named the groups in order of increasing complexity. • For example, if one of the alkyl groups is methyl and the other is t- butyl, the current common name should be "t-butyl methyl ether,’’ • But most chemists use the older common name, "methyl t-butyl ether" • If both groups are methyl, the name is "dimethyl ether.’’ • If just one alkyl group is described in the name, it implies the ether is symmetrical, as in "ethyl ether." STEP 5: Chemical Structure of Ethers (15 minutes). • Ethers are a class of organic compounds that contain an ether group. • An ether group is an oxygen atom connected to two alkyl or aryl groups. • They follow the general formula R-O-R’. The C-O-C linkage is characterized by bond angles of 104.5 degrees, with the C-O distances being about 140 pm. • The oxygen of the ether is more electronegative than the carbons. • Thus, the alpha hydrogens are more acidic than in regular hydrocarbon chains. [pic] STEP 6: Chemical Properties of Ethers (15 minutes). |Activity: Buzzing (5minutes) | | | |ASK students to pair up and buzz on the following question for 5 | |minutes | | | |What are the chemical properties of Ethers? | | | |ALLOW pairs to respond on the question | | | |WRITE their response on the flip chart/board | | | |CLARIFY and SUMMARIZE by using the content in