MPharm Programme PHA114 Carbonyl Compounds 1 PDF

WEEK WEEK 17 17...

WEEK WEEK 17 17 Carbonyl Compounds C O MPharm Programme Carbonyl Group: – many different kinds of carbonyl group PHA114 –many different reactions of carbonyl groups Carbonyl groups can undergo: Carbonyl Compounds 1 – nucleophilic addition reactions aldehydes and ketones Dr. Matt Smith – nucleophilic addition elimination reactions carboxylic acid derivatives Slide 1 MPharm PHA114 Carbonyl compounds 1 Slide 2 MPharm PHA114 Carbonyl compounds 1 WEEK O O WEEK ALDEHYDE CARBOXYLIC ACID 17 R H R O H 17 O O O KETONE CARBOXYLATE SALT R R1 R O R O Procaine Lidocaine Cocaine O O ACYL HALIDE Podophyllotoxin X = Cl (Br, I) ESTER R1 R X R O O O O ANHYDRIDE R O R1 LACTONE O (cyclic este r) ~ carbonyl groups Penicillin N Captopril Enalapril - amide O O - Ketore PRIMARY AMIDE THIOESTER R1 - ester R NH2 R S - ddehyde 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 Dactinomycin LACTAM N N (cyclic amide) Erythromycin Vincristine penicillin - interact with well well Slide 3 MPharm PHA114 Carbonyl compounds 1 Slide 4 MPharm PHA114 Carbonyl compounds 1 WEEK WEEK 17 17 Carbonyl Structure C O Carbonyl Structure C O Trigonal planar sp2 carbon C=O bond is shorter, stronger, and more polar than C=C bond in alkenes 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 shorter I stronger overlap Slide 5 MPharm PHA114 Carbonyl compounds 1 Slide 6 MPharm PHA114 Carbonyl compounds 1 WEEK WEEK 17 Hydrogen Bonding 17 Probably the most important of all non-covalent interactions ~ carbonyl nucleophile ↓ Acidity Short range, directional, inter or intramolecular non-bonded interaction carbon Non-bonded interaction between a hydrogen atom bonded to an electronegative atom Important for drug molecule – receptor interactions ↓ electrostatic, curly I arrow Carboxylic acids are weak = acids (proton donors) don't dissociate completely Carboxylic acids transfer a proton to water (proton acceptor) to give H3O+ and carboxylate anions RCO2 (H3O+ is a much stronger acid) ? etc. #-I stocking leave pulls ↓ Selections  want to  Hydrogen i 90 O H Acceptor R  H  onor   C= O  Il R strong H H band acceptor O H 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 7 MPharm PHA114 Carbonyl compounds 1 Slide 8 MPharm PHA114 Carbonyl compounds 1 WEEK WEEK 17 17 Acidity of Carboxylic Acids Fraction Ionised - pH Dependency For a weak acid HA : Acidity of carboxylic acids higher than alcohols although both compounds Ka [A - ][H ] containing an OH group, why: deprotonate HA H+ + A- Ka  [HA] ↓ resonance stabilisation of the carboxylate anion – H atom is lost more easily from pH = pKa -4 … 0.01% ionised carboxylic acid. delocdisestable - => more everywhere - charge ok/no dcohol we pH = pKa -3 … 0.1% ionised – carboxylate ion is the conjugate base of carboxylic acid 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) erywhere more O O O 100 H3C O H3C O H3C O % of HA ionised = 1  antilog10(pKa – pH) Slide 9 MPharm PHA114 Carbonyl compounds 1 Slide 10 MPharm PHA114 Carbonyl compounds 1 WEEK WEEK 17 17 Electron-withdrawing groups (EWG) Consequences? 161 effects carboxylic acids acidity O O O EWG O EWG O EWG O electro-withdrawing 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 not interact Therefore EWG increases acidity of carboxylic acid in the some way ? - lose electrostatic reaction Interact I Slide 11 MPharm PHA114 Carbonyl compounds 1 Slide 12 MPharm PHA114 Carbonyl compounds 1 WEEK WEEK R 17 Electron-donating groups (EDG) 17 Carboxylic Acid Derivatives C O The group bonded to the acyl carbon determines the class of compound: effects carboxylic acids acidity ~ No drew Need to mechanism 24" X prepared from acid chloride via O O O nucleophilic acyl substituted reactions EDG O EDG O EDG O SOCl2 O O O O O O or POCl3 O good or PCl3 leaving R2 EDG DECREASES the acidity of the carboxylic acid because: R1 Ogroup Cl R 1 O R2 R1 O R1 NHR2 R1 O R1 OH EDG pushes electrons pushes e-density carbonyl > - In to Carboxylic acid acid chloride anhydride ester amide carboxylate Negative charge less delocalised acidic hydrolysis Most reactive Order of reactivity Least reactive Negative charge is less resonance stabilised Carboxylate less willing to loose H Therefore, EDG reduces acidity of carboxylic acid Acid chloride may be interconverted via nucleophilic acyl substitution reactions Cl = EWG; more Cl atoms, more acidic the carboxylic acid O O O O All can be converted to the parent carboxylic acid by acidic or basic hydrolysis H Cl Cl Cl Carboxylic acids, esters and amides are common in nature and pharmaceuticals OH OH OH OH H H Cl Cl H H H Cl pKa = 4.75 pKa = 2.85 pKa = 1.48 pKa = 0.64 Nitriles R-C N (hydrolysis gives carboxylic acids, via primary amides) Increase in acidity Slide 13 MPharm PHA114 Carbonyl compounds 1 Slide 14 MPharm PHA114 Carbonyl compounds 1 WEEK Thioesters and Acyl Phosphates: Biological Carboxylic WEEK 17 2 phosphate 17 Acid Derivatives derivative of ? Nucleophilic carboxyl substitution in nature often involves a thioester or acyl phosphate derivative Reactions at the Carbonyl Carbon These have unique binding properties and are readily activated by enzymes The carbonyl group is polar – oxygen is more electronegative than carbon The carbonyl carbon is electrophilic – the carbonyl carbon is susceptible to nucleophilic attack 3D * dipole + NH2 across the membrane N NH2 N H H N O OH O O N N N N N O P O P O O O O ↳ smal changing C O N H3C S O O O O P O P O P O N - ↑ electron In electron density O O H3C CH3 density O O O O O O OH O P O OH OH SCoA - H3C - O adenosinA-5 '-t riphosphat e Acetyl coenzyme A ATP 1 ↓ electron density Slide 15 MPharm PHA114 Carbonyl compounds 1 Slide 16 MPharm PHA114 Carbonyl compounds 1 WEEK WEEK 17 17 Nucleophilic For good nucleophiles: Addition Reactivity of Carbonyl Compounds carbonyl group is * Drow the mechanism - EXAM Reactions I sufficiently electrophilic to undergo efficient reaction Reactivity of aldehydes, ketones, carboxylic acids, esters and amides can be Aldehydes enhanced by protonation of the carbonyl oxygen (to make the conjugate acid) Ketones – the carbonyl carbon becomes more electrophilic – the carbonyl carbon is more susceptible to nucleophilic attack C is more electrophilic ()after protonation 8t ↑ H H H C O H OH2 C O C O C O H H product C O Nu C O will not have charge ! Nu remove For weak nucleophiles: Nucleophile > - keep going on until It gone I carbonyl group requires activation acid catalysis Slide 17 MPharm PHA114 Carbonyl compounds 1 Slide 18 MPharm PHA114 Carbonyl compounds 1 WEEK WEEK 17 17 Reversibility Nucleophiles Basic Conditions : Nucleophiles can be negatively charged ( : Nu) or neutral ( : NuH) at the reaction site The overall charge on the nucleophilic species is not considered u Acidic Conditions : (Note : “H-” only exists under extreme conditions; it is delivered from a hydride donor) Slide 19 MPharm PHA114 Carbonyl compounds 1 Slide 20 MPharm PHA114 Carbonyl compounds 1 WEEK WEEK 17 17 Reactions at the Carbonyl Carbon Bürgi-Dunitz angle MPharm Programme PHA114 Carbonyl Compounds 2 Aldehyde Ketone Dr. Matt Smith Less steric crowding More steric crowding less bulky-bulky - efficient ( no (Note : nucleophile may approach from above or below plane of C=O) Slide 21 MPharm PHA114 Carbonyl compounds 1 Slide 1 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 17 Relative Reactivity of Reactions at the Carbonyl Carbon Aldehydes and Ketones Electron pair moves from C=O bond to electronegative oxygen atom producing Aldehydes are generally more reactive than ketones in nucleophilic addition reactions tetrahedral alkoxide ion intermediate The transition state for addition is less crowded and lower in energy for an aldehyde Formation of new bonds increases steric crowding than for a ketone Introduction of a chiral centre (carbonyl carbon sp2 -> tetrahedral carbon sp3) – aldehydes : one large substituent bonded to the C=O – ketones : two large substituent bonded to the C=O Good nucleophiles : “hydride”, alkynyl anions, alkoxides Alkyl groups are electron releasing – aldehyde has a greater partial positive charge on carbonyl carbon than a ketone I - bond breaks – the aldehyde carbon is more electrophilic than the ketone carbon wecker tetrahedral alkoxide - ↓ ion intermediate - If RIFRz C= chird centre nucleophile may approach from above or below plane of C=O leading to chiral centre IF all four atoms on the C atom is different. Slide 2 MPharm PHA114 Carbonyl compounds 2 Slide 3 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 17 Reduction of Cyanohydrin Formation cyanide ~ nucleophile (good) * Remember Rules ! Aldehydes and Ketones Hydride Addition converts R-C=O to R-C-OH. => back to the dcohol Donors of “hydride ion” (“H-”) = sodium borohydride (NaBH4) or lithium aluminium addition -ve move to oxygen density hydride (LiAlH4). of cyanide Protonation yields the alcohol (from solvent or acid) [tetrahedral] – aldehyde reduced to primary alcohol kick out group the leaving reform – ketone reduced to secondary alcohol H (a) & double bond elimination intermediate in B H ↳ & of cyanide Trigonal planar sp2 O Tetrahedral O H H Na OBH3 H O H OH L oxygen double sp3 bond dkyl group break H competing= not leaving [ketone ] R1 R2 R1 H a group H R2 "protic solvent" R1 R1 R2 R2 H - Y protonate (b) cyanohydrin Na B H formation H H Stereochemistry nucleophile ↓ carbonyl Carbon Y kick out the oxygen = break > leaving 1 mole NaBH4 can reduce 4 molegroup - ketone (0.25 mol NaBH4 reduces 1 mole ketone) Slide 4 MPharm PHA114 Carbonyl compounds 2 Slide 5 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 Biological Reduction 17 Oxidation of Aldehydes Hydride Transfer Ikreb's cycle) O NH2 Aldehydes are easily oxidised to carboxylic acids N NH2 N O O – –CHO hydrogen abstracted during oxidation N N N O P O P O lose 4- – Chemically, with an oxidising agent: CrO3, KMnO4, HNO3 O O O O * nucleophile Ketones are relatively inert toward oxidation like & cannot OH OH OH OH = NcBH4 Oxidise nicotinamide adenine dinucleotide further NADH ↑ NADH cytochrome B5 reductase Ltakepyruvate muscle pain wit Slide 6 MPharm PHA114 Carbonyl compounds 2 Slide 7 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 * curly arrow mechanism 17 Biological Relevance: Aldehydes / Ketones Alcoholysis Cyclisation of D-Glucose H OH2 Intramolecular reaction results in cyclisation: ↓ M here = Adehyde nucleophilic attack 1 CHO 6 CH2OH 6 CH2OH 2 H OH 5 O 3 5 O OH HO H 4 1 4 1 OH H 4 OH OH deprotonate 2 2 Il OH OH OH H30t formed 3 H 5 OH 3 OH OH 6 CH2OH 7 -anomer open-chain form -anomer 36% < 0.05% yhemiacetal 64% ring-opened = - Half of d Anomers: glucose zoR groups Two sugars that differ in configuration at the carbon that is the C=O in the open chain form = o n the s c re carbon X reprotonated (called the anomeric carbon). on makes The -OH group that forms at C-1 can be AXIAL or EQUATORIAL placed resulting in two - = better leaving group structural forms Slide 8 MPharm PHA114 Carbonyl compounds 2 Slide 9 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 17 Cyclisation of D-Glucose * BIOCHEM X sweetener Nucleophilic Acyl Substitution 28" in tablet form , related etc. Stabilise R + - -H+   C=O L good /leaving group L stabilise & leave 5 1 All carboxylic acid derivatives react by the same general mechanism # polarity of the carbonyl group Carboxylic acid derivatives have an acyl carbon bonded to a group that can leave Nucleophile adds to the carbonyl carbon to form a tetrahedral anionic intermediate not flot Leaving group is expelled to generate a new carbonyl compound, leading to substitution overall, an addition-elimination sequence the tetrahedral intermediate eliminates the weakest base Some carboxylic acid derivatives require acid catalysis to promote reaction Are other ring sizes possible? Slide 10 MPharm PHA114 Carbonyl compounds 2 Slide 11 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 17 Reactivity Inductive Effects Reactivity decreases as leaving group becomes more basic A weaker base is a more electronegative base pKa conjugate – better able to accommodate its own negative charge acid Weaker bases are better at inductive electron withdrawal from carbonyl carbon – increases electrophilicity of carbonyl carbon = more cidic -1.7 – more electrophilic carbonyl groups are more reactive to addition acid halides are most reactive, amides are least ~ 3-5 – carbonyl carbon is more susceptible to nucleophilic attack – first step of acyl nucleophilic substitution is easier ~ 15-16  - no good ~ 38-40 O leaving +C request relatively more E ! saying To leave R Y A more reactive acid derivative can be easily converted into a less reactive one It is much harder to convert a less reactive acid derivative into a more reactive one Slide 12 MPharm PHA114 Carbonyl compounds 2 Slide 13 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 Orbital Overlap in 17 Activation of Carboxylic Acids Carboxylic Acid Derivatives Convert the OH group into a better leaving group Orbitals Overlap – an acid halide or acid anhydride  – activated forms of the carboxylic acid Empty * – analogous to biological processes! Lone Pair orbitial Chloride is a good leaving group, so undergoes acyl substitution easily Y O C – not useful as pharmaceutical drugs – too reactive – useful in synthesis of drug molecules to give esters and amides R isn't To synthesise acid chlorides by reacting the carboxylic acid with thionyl chlorid really electro - (SOCl2) - + ve The more effective the orbital overlap (resonance): resonance · bang formed the more stable the carboxylic acid derivative the less reactive the carboxylic acid derivative most effective for amides - amides are the least reactive Slide 14 MPharm PHA114 Carbonyl compounds 2 Slide 15 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 17 Acid Chlorides - Reactions Acid Chlorides – Reactions (Hydrolysis) Nucleophilic acyl substitution via addition (of nucleophile) and elimination (of chloride) reaction Acid chlorides react with water to yield carboxylic acids (hydrolysis reaction) Halogen replaced by nuclephile Water attacks the acid chloride carbonyl group Hydrolysis yields a carboxylic acid Tetrahedral intermediate undergoes elimination of Cl- and loss of H+ to give the Reduction yields a primary alcohol product carboxylic acid avad - al nucleophile water - mechanistically to make M m the SAME ! this ! to make - - - availability better ! Replace H2O with ROH -> ester - Replace H2O with RNH2 -> secondary amide Slide 16 MPharm PHA114 Carbonyl compounds 2 Slide 17 MPharm PHA114 Carbonyl compounds 2 WEEK WEEK 17 18 Acid Chlorides – Reactions (-> Esters/Amides) carboxylic acid => T Esters are produced in the reaction of acid chlorides with alcohols in the presence of a tertiary amine base (e.g. triethylamine, pyridine) or NaOH MPharm Programme Amides result from the reaction of acid chlorides with NH3 to give primary (RNH2) and secondary (R2NH) amines – HCl is neutralised by the amine or base Same general reaction mechanism PHA114 N N Carbonyl Compounds 3 N reduction O OH O Cl O O O SOCl2 HO Raney Ni N N N H2N O O O O O O O - 4 n itro benzo ic ac id proca ine O O Cl O N Dr. Matt Smith Cl HN Cl NH2 NH NH chloroacetyl chloride diethylamine - 2,6 dimethylaniline lidocaine Slide 18 MPharm PHA114 Carbonyl compounds 2 Slide 1 MPharm PHA114 Carbonyl compounds 3 WEEK WEEK c.f. Slide 42 / 51 18 18 Anhydrides – Reactions (-> Esters) Anhydrides – Reactions (-> Esters) Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines methanol addition/elimination [ddition product] Ccetic add amide elimination (vinegar) The same general mechanism applies to reactions of acid anhydrides with: water, hydroxide, alcohols, alkoxides, 1o and 2o amines