PHA114 Carbonyl Compounds 1 PDF

WEEK 17 MPharm Programme PHA114 Carbonyl Compounds 1 Dr. Matt Smith Slide 1 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Carbonyl Compounds C O Carbonyl Group...

WEEK 17 MPharm Programme PHA114 Carbonyl Compounds 1 Dr. Matt Smith Slide 1 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Carbonyl Compounds C O Carbonyl Group: – many different kinds of carbonyl group –many different reactions of carbonyl groups Carbonyl groups can undergo: – nucleophilic addition reactions aldehydes and ketones – nucleophilic addition elimination reactions carboxylic acid derivatives Slide 2 MPharm PHA114 Carbonyl compounds 1 WEEK O O ALDEHYDE CARBOXYLIC ACID 17 R H R O H O O O KETONE CARBOXYLATE SALT R R1 R O R O O O ACYL HALIDE X = Cl (Br, I) ESTER R1 R X R O O O O ANHYDRIDE R O R1 LACTONE O (cyclic este r) O O PRIMARY AMIDE THIOESTER R1 R NH2 R S O O SECONDARY AMIDE R1 MONO PHOSPHATE P R R N O O H O O TERTIARY AMIDE R1 R N R2 NITRILE R C N O O H R LACTAM N N ( clic am ide) c y Slide 3 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Procaine Lidocaine Cocaine Podophyllotoxin Penicillin N Captopril Enalapril Dactinomycin Erythromycin Vincristine Slide 4 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Carbonyl Structure C O Trigonal planar sp2 carbon Trigonal planar sp2 oxygen C-O  bond between sp2 orbitals on carbon and oxygen  bond between substituents and sp2 orbital on carbon All  bonds lie in same plane ~120° apart C-O  bond between parallel p orbitals on carbon and oxygen Slide 5 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Carbonyl Structure C O C=O bond is shorter, stronger, and more polar than C=C bond in alkenes Slide 6 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Hydrogen Bonding Probably the most important of all non-covalent interactions Short range, directional, inter or intramolecular non-bonded interaction Non-bonded interaction between a hydrogen atom bonded to an electronegative atom Important for drug molecule – receptor interactions   O H  H  R   C= O  R H O H  Slide 7 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Acidity Carboxylic acids are weak acids (proton donors) Carboxylic acids transfer a proton to water (proton acceptor) to give H3O+ and carboxylate anions RCO2 (H3O+ is a much stronger acid) Acidity constant, Ka, is 10-3 - 10-5 for a typical carboxylic acid pKa values for most aliphatic and aromatic carboxylic acids fall within the range 3 – 5 Slide 8 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Acidity of Carboxylic Acids Acidity of carboxylic acids higher than alcohols although both compounds containing an OH group, why: resonance stabilisation of the carboxylate anion – H atom is lost more easily from carboxylic acid. – carboxylate ion is the conjugate base of carboxylic acid O O O H3C O H3C O H3C O Slide 9 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Fraction Ionised - pH Dependency For a weak acid HA : Ka [A - ][H ] HA H+ + A- Ka  [HA] pH = pKa -4 … 0.01% ionised pH = pKa -3 … 0.1% ionised pH = pKa -2 … 1% ionised pH = pKa -1 … 10% ionised pH = pKa … 50% ionised pH = pKa +1 … 90% ionised pH = pKa +2 … 99% ionised pH = pKa +3 … 99.9% ionised increasing pH pH = pKa +4 … 99.99% ionised 1 fraction of HA ionised = 1  antilog10(pKa – pH) 100 % of HA ionised = 1  antilog10(pKa – pH) Slide 10 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Consequences? Slide 11 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Electron-withdrawing groups (EWG) effects carboxylic acids acidity O O O EWG O EWG O EWG O EWG increases the acidity of the carboxylic acid because: EWG pulls electrons Negative charge delocalises more Negative charge is more resonance stabilised Carboxylate more willing to loose H Therefore EWG increases acidity of carboxylic acid Slide 12 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Electron-donating groups (EDG) effects carboxylic acids acidity O O O EDG O EDG O EDG O EDG DECREASES the acidity of the carboxylic acid because: EDG pushes electrons Negative charge less delocalised Negative charge is less resonance stabilised Carboxylate less willing to loose H Therefore, EDG reduces acidity of carboxylic acid Cl = EWG; more Cl atoms, more acidic the carboxylic acid O O O O H Cl Cl Cl OH OH OH OH H H Cl Cl H H H Cl pKa = 4.75 pKa = 2.85 pKa = 1.48 pKa = 0.64 Increase in acidity Slide 13 MPharm PHA114 Carbonyl compounds 1 WEEK 17 R Carboxylic Acid Derivatives The group bonded to the acyl carbon determines the class of compound: C O X prepared from acid chloride via nucleophilic acyl substituted reactions SOCl2 O O O or POCl3 O O O O or PCl3 R2 R1 Cl R1 O R2 R1 R1 NHR2 R1 O R1 O OH acid chloride anhydride ester amide carboxylate Carboxylic acid Most reactive Order of reactivity Least reactive Acid chloride may be interconverted via nucleophilic acyl substitution reactions All can be converted to the parent carboxylic acid by acidic or basic hydrolysis Carboxylic acids, esters and amides are common in nature and pharmaceuticals Nitriles R-C N (hydrolysis gives carboxylic acids, via primary amides) Slide 14 MPharm PHA114 Carbonyl compounds 1 WEEK Thioesters and Acyl Phosphates: Biological Carboxylic 17 Acid Derivatives Nucleophilic carboxyl substitution in nature often involves a thioester or acyl phosphate derivative These have unique binding properties and are readily activated by enzymes NH2 N NH2 N H H N O OH O O N N N N N O P O P O O O O H3C S N N O O O O P O P O P O O O H3C CH3 O O O O O O OH O P O OH OH H3C SCoA O - '- - adenosinA 5 t riphosphat e Acetyl coenzyme A ATP Slide 15 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Reactions at the Carbonyl Carbon The carbonyl group is polar – oxygen is more electronegative than carbon The carbonyl carbon is electrophilic – the carbonyl carbon is susceptible to nucleophilic attack + C O - Slide 16 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Reactivity of Carbonyl Compounds Reactivity of aldehydes, ketones, carboxylic acids, esters and amides can be enhanced by protonation of the carbonyl oxygen (to make the conjugate acid) – the carbonyl carbon becomes more electrophilic – the carbonyl carbon is more susceptible to nucleophilic attack C is more electrophilic ()after protonation H H H C O H OH2 C O C O C O H H C O Nu C O Nu Slide 17 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Nucleophilic For good nucleophiles: Addition carbonyl group is Reactions sufficiently electrophilic to undergo efficient reaction Aldehydes Ketones For weak nucleophiles: carbonyl group requires activation acid catalysis Slide 18 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Reversibility Basic Conditions : Acidic Conditions : Slide 19 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Nucleophiles Nucleophiles can be negatively charged ( : Nu) or neutral ( : NuH) at the reaction site The overall charge on the nucleophilic species is not considered (Note : “H-” only exists under extreme conditions; it is delivered from a hydride donor) Slide 20 MPharm PHA114 Carbonyl compounds 1 WEEK 17 Reactions at the Carbonyl Carbon Bürgi-Dunitz angle Aldehyde Ketone Less steric crowding More steric crowding (Note : nucleophile may approach from above or below plane of C=O) Slide 21 MPharm PHA114 Carbonyl compounds 1