PHA114 Carbonyl Compounds 2 PDF

WEEK 17 MPharm Programme PHA114 Carbonyl Compounds 2 Dr. Matt Smith Slide 1 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Reactions at the Carbonyl Carbon Electron pair moves from C=O bond...

WEEK 17 MPharm Programme PHA114 Carbonyl Compounds 2 Dr. Matt Smith Slide 1 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Reactions at the Carbonyl Carbon Electron pair moves from C=O bond to electronegative oxygen atom producing tetrahedral alkoxide ion intermediate Formation of new bonds increases steric crowding Introduction of a chiral centre (carbonyl carbon sp2 -> tetrahedral carbon sp3) Good nucleophiles : “hydride”, alkynyl anions, alkoxides tetrahedral alkoxide ion intermediate 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 WEEK 17 Relative Reactivity of Aldehydes and Ketones Aldehydes are generally more reactive than ketones in nucleophilic addition reactions The transition state for addition is less crowded and lower in energy for an aldehyde than for a ketone – aldehydes : one large substituent bonded to the C=O – ketones : two large substituent bonded to the C=O Alkyl groups are electron releasing – aldehyde has a greater partial positive charge on carbonyl carbon than a ketone – the aldehyde carbon is more electrophilic than the ketone carbon Slide 3 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Cyanohydrin Formation addition of cyanide (a) elimination of cyanide (b) cyanohydrin formation Slide 4 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Reduction of Aldehydes and Ketones Hydride Addition converts R-C=O to R-C-OH. Donors of “hydride ion” (“H-”) = sodium borohydride (NaBH4) or lithium aluminium hydride (LiAlH4). Protonation yields the alcohol (from solvent or acid) – aldehyde reduced to primary alcohol – ketone reduced to secondary alcohol H B H Trigonal planar H O O Tetrahedral H Na OBH3 OH sp2 O H H sp3 H H R1 R2 H R1 "protic solvent" R1 R1 R2 R2 R2 H Na B H H H Stereochemistry 1 mole NaBH4 can reduce 4 mole ketone (0.25 mol NaBH4 reduces 1 mole ketone) Slide 5 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Biological Reduction Hydride Transfer O NH2 N NH2 N O O N N N O P O P O O O O O OH OH OH OH nicotinamide adenine dinucleotide NADH NADH cytochrome B5 reductase Slide 6 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Oxidation of Aldehydes Aldehydes are easily oxidised to carboxylic acids – –CHO hydrogen abstracted during oxidation – Chemically, with an oxidising agent: CrO3, KMnO4, HNO3 Ketones are relatively inert toward oxidation Slide 7 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Aldehydes / Ketones Alcoholysis H OH2 Slide 8 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Biological Relevance: Cyclisation of D-Glucose Intramolecular reaction results in cyclisation: 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 2 2 OH OH 5 OH 3 H OH 3 OH OH 6 CH2OH -anomer open-chain -anomer 36% < 0.05% 64% Anomers: Two sugars that differ in configuration at the carbon that is the C=O in the open chain form (called the anomeric carbon). The -OH group that forms at C-1 can be AXIAL or EQUATORIAL placed resulting in two structural forms Slide 9 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Cyclisation of D-Glucose -H+ 5 1 Are other ring sizes possible? Slide 10 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Nucleophilic Acyl Substitution R + -   C=O L 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 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 Slide 11 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Reactivity Reactivity decreases as leaving group becomes more basic pKa conjugate acid -1.7 ~ 3-5 ~ 15-16 ~ 38-40 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 WEEK 17 Inductive Effects A weaker base is a more electronegative base – better able to accommodate its own negative charge Weaker bases are better at inductive electron withdrawal from carbonyl carbon – increases electrophilicity of carbonyl carbon – more electrophilic carbonyl groups are more reactive to addition acid halides are most reactive, amides are least – carbonyl carbon is more susceptible to nucleophilic attack – first step of acyl nucleophilic substitution is easier  O +C R Y Slide 13 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Orbital Overlap in Carboxylic Acid Derivatives Orbitals Overlap Empty  * Lone Pair orbitial Y O C R The more effective the orbital overlap (resonance): 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 WEEK 17 Activation of Carboxylic Acids Convert the OH group into a better leaving group – an acid halide or acid anhydride – activated forms of the carboxylic acid – analogous to biological processes! Chloride is a good leaving group, so undergoes acyl substitution easily – not useful as pharmaceutical drugs – too reactive – useful in synthesis of drug molecules to give esters and amides To synthesise acid chlorides by reacting the carboxylic acid with thionyl chlorid (SOCl2) Slide 15 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Acid Chlorides - Reactions Nucleophilic acyl substitution via addition (of nucleophile) and elimination (of chloride) reaction Halogen replaced by nuclephile Hydrolysis yields a carboxylic acid Reduction yields a primary alcohol Slide 16 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Acid Chlorides – Reactions (Hydrolysis) Acid chlorides react with water to yield carboxylic acids (hydrolysis reaction) Water attacks the acid chloride carbonyl group Tetrahedral intermediate undergoes elimination of Cl- and loss of H+ to give the product carboxylic acid Replace H2O with ROH -> ester Replace H2O with RNH2 -> secondary amide Slide 17 MPharm PHA114 Carbonyl compounds 2 WEEK 17 Acid Chlorides – Reactions (-> Esters/Amides) 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 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 N N 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 Cl HN Cl NH2 NH NH chloroacetyl chloride diethylamine - 2,6 dimethylaniline lidocaine Slide 18 MPharm PHA114 Carbonyl compounds 2