PHA114 Carbonyl Compounds 3 PDF

WEEK 18 MPharm Programme PHA114 Carbonyl Compounds 3 Dr. Matt Smith Slide 1 MPharm PHA114 Carbonyl compounds 3 WEEK c.f. Slide 42...

WEEK 18 MPharm Programme PHA114 Carbonyl Compounds 3 Dr. Matt Smith Slide 1 MPharm PHA114 Carbonyl compounds 3 WEEK c.f. Slide 42 / 51 18 Anhydrides – Reactions (-> Esters) The same general mechanism applies to reactions of acid anhydrides with: water, hydroxide, alcohols, alkoxides, 1o and 2o amines Anhydrides are less reactive than acid chlorides – they react more slowly Slide 2 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Anhydrides – Reactions (-> Esters) Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines Slide 3 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Anhydrides in nature Slide 4 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Acid-catalysed esterification Slide 5 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Thioesters: Biological Carboxylic Acid Derivatives Nucleophilic carboxyl substitution in nature often involves a thioester – unique binding properties and are readily activated by enzymes Slide 6 MPharm PHA114 Carbonyl compounds 3 WEEK Base Induced Ester Hydrolysis 18 Acid Catalysed Ester Hydrolysis base is reactant and is consumed reaction is essentially irreversible ester hydrolysis is common in biological chemistry Slide 7 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Esters - Reactions (Transesterification) One alkoxy group can be replaced by another with acid or base catalyst Use large excess of preferred alcohol Slide 8 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Acetylcholinesterase Acetylcholine – Responsible for nerve-impulse transmission in animals – After interaction with receptor it must be degraded to prevent further interaction – Hydrolysis to acetate and choline by acetylcholinesterase (a serine esterase) – Turnover of 10000 molecules per second at a single active site – Key target for drug interaction (cholinesterase inhibitors) Slide 9 MPharm PHA114 Carbonyl compounds 3 WEEK c.f. Slide 42 18 Esters - Reactions (Aminolysis) Ammonia, 1o and 2o amines react with esters to form amides Slide 10 MPharm PHA114 Carbonyl compounds 3 WEEK c.f. Slide 42 18 Esters - Reactions (Reduction) Reduction with LiAlH4 yields two alcohols Hydride ion adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde Aldehydes are more reactive than esters Reduction of the aldehyde gives the primary alcohol Slide 11 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Amides Amides are very unreactive – do not react with water, alcohols, carboxylate ions, halide ions – incoming nucleophile is a weaker base than the leaving group – more stable in vivo than esters – metabolic hydrolysis can occur via amidase enzymes Lone pair on nitrogen is stabilised – less reactive Proteins are composed of amino acids linked together by amide bonds!! Slide 12 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Amides Resonance imparts significant double-bond character to C—N bond in amides Activation energy for rotation about C—N bond is 75-85 kJmol-1 C—N bond distance is ~135 pm in amides versus normal single-bond distance of ~147 pm in amines Slide 13 MPharm PHA114 Carbonyl compounds 3 WEEK c.f. Slide 56 18 Amides - Reactions (Acidic Hydrolysis) Slide 14 MPharm PHA114 Carbonyl compounds 3 WEEK c.f. Slide 42 18 Amides - Reactions (Basic Hydrolysis) Addition of hydroxide and loss of amide ion Slide 15 MPharm PHA114 Carbonyl compounds 3 WEEK 18 β-Lactams Highly reactive, 4-membered amide ring Found in antibiotics isolated from fungi – Penicillins compounds produced by various species of Penicillium many semi-synthetic penicillins, produced by converting one antibiotic into another – Cephalosporins compounds produced by various species of Cephalosporium many semi-synthetic cephalosporins (1st/2nd/3rd/4th generation) – Also carbapenems, monobactams Slide 16 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Semi-Synthetic Penicillins Penicillin G manufactured commercially using Penicillium chrysogenum secondary metabolite produced towards end of growth period Many different penicillins in clinical use: Differ only in the R group (note, prodrugs have moidified carboxylic acid groups) e.g. penicillin G, penicillin O, penicillin V, ampicillin, bacampicillin, pivampicillin, amoxicillin, oxacillin, cloxacillin, nafcillin, flucloxacillin, dicloxacillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin …. Differ in organism which they are most effective, differ in resistance to penicillinase, differ in acid sensitivity Slide 17 MPharm PHA114 Carbonyl compounds 3 WEEK 18 β-lactams inhibit the cross-linking mechanism during biosynthesis of bacterial cell wall … growing bacteria die as cannot produce functional cell walls Slide 18 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Amides - Reactions (Reduction) Reduced by LiAlH4 to an amine rather than an alcohol (c.f. esters) Converts C=O → CH2 (lactams give cyclic amines) Loss of carbonyl oxygen as an aluminate anion to give an iminium ion intermediate which is reduced to the amine Slide 19 MPharm PHA114 Carbonyl compounds 3 WEEK 18 Further Reading/References Bruice, Organic Chemistry – Carbonyl Compounds I – Carbonyl Compounds II Organic Chemistry – Relevant chapters in books by Clayden, Crowe, McMurray, Solomons, Wade, Fox, etc. Slide 20 MPharm PHA114 Carbonyl compounds 3