Organic Lecture Series Aldehydes And Ketones Chap 16 111 Organic Lecture Series IUPAC names • the parent alkane is the longest chain that contains the carbonyl group • for ketones, change the suffix -e to -one • number the chain to give C=O the smaller number • the IUPAC retains the common names acetone, acetophenone, and benzophenone O O O O Propanone Acetophenone Benzophenone 1-Phenyl-1-pentanone (Acetone) Commit to memory 222 Organic Lecture Series Common Names – for an aldehyde , the common name is derived from the common name of the corresponding carboxylic acid O O O O HCH HCOH CH3 CH CH3 COH Formaldehyde Formic acid Acetaldehyde Acetic acid – for a ketone , name the two alkyl or aryl groups bonded to the carbonyl carbon and add the word ketone O O O Ethyl isopropyl ketone Diethyl ketone Dicyclohexyl ketone 333 Organic Lecture Series Drawing Mechanisms • Use double-barbed arrows to indicate the flow of pairs of e - • Draw the arrow from higher e - density to lower e - density i.e. from the nucleophile to the electrophile • Removing e - density from an atom will create a formal + charge • Adding e - density to an atom will create a formal - charge • Proton transfer is fast (kinetics) and usually reversible 444 Organic Lecture Series Reaction Themes One of the most common reaction themes of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound (intermediate). - R O Nu - + C O Nu C R R R Tetrahedral carbonyl addition compound 555 Reaction Themes Organic Lecture Series A second common theme is reaction with a proton or other Lewis acid to form a resonance- stabilized cation-- – protonation increases the electron deficiency of the carbonyl carbon and makes it more reactive toward nucleophiles R fast R + R - + CO + H-B B + CO H CO H R R R R O-H - + slow B + H-Nu + CO H Nu C + H-B R R R Tetrahedral carbonyl addition compound 666 Organic Lecture Series – often the tetrahedral product of addition to a carbonyl is a new chiral center – if none of the starting materials is chiral and the reaction takes place in an achiral environment, then enantiomers will be formed as a racemic mixture Approach from the top face Nu Nu O OH R R R' + R' - R H3 O Nu CO + + R' R R R' R' O OH Nu Nu Approach from A new chiral A racemic mixture the bottom face center is created 777 Organic Lecture Series Addition of C Nucleophiles Addition of carbon nucleophiles is one of the most important types of nucleophilic additions to a C=O group – a new carbon-carbon bond is formed in the process – Focus on addition of these carbon nucleophiles: RMgX RLi RC C - - C N A Grignard An organolithium An alkyne Cyanide ion reagent reagent anion 888 Organic Lecture Series Grignard Reagents – addition of a Grignard reagent to + formaldehyde followed by H 3O gives a 1° alcohol O ether CH3 CH2 -MgBr + H-C-H Formaldehyde - + O [ MgBr] OH HCl 2+ CH3 CH2 -CH2 CH3 CH2 -CH2 + Mg H2 O A magnesium 1-Propanol alkoxide (a 1° alcohol) 999 Organic Lecture Series Grignard Reagents – addition to any other RCHO gives a 2°alcohol MgBr O ether + H Acetaldehyde (an aldehyde) - + O [ MgBr] OH HCl + Mg2+ H2 O A magnesium 1-Cyclohexylethanol alkoxide (a 2° alcohol; (racemic) 101010 Organic Lecture Series Grignard Reagents – addition to a ketone gives a 3°alcohol O ether Ph-MgBr + Phenyl- Acetone magnesium (a ketone) bromide - + OH O [ MgBr] HCl + Mg2+ Ph H2 O Ph A magnesium 2-Phenyl-2-propanol alkoxide (a 3° alcohol) 111111 Organic Lecture Series Problem: 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination. OH C-CH2 CH3 CH3 121212 Organic Lecture Series O A Simple Retrosynthetic Analysis CH3 OH O CH3 CH3 O CH3 131313 Organic Lecture Series 141414 Organic Lecture Series Addition Reactions to Carbonyl Compounds Note: Water can also be added to ketones & aldehydes. 151515 Organic Lecture Series Organolithium Reagents Organolithium compounds are generally more reactive in C=O addition reactions than RMgX, and typically give higher yields O- Li+ O OH Li + HCl H2 O Phenyl- 3,3-Dimethyl-2- A lithium alkoxide 3,3-Dimethyl-2-phenyl- lithium butanone (racemic) 2-butanol (racemic) 161616 Organic Lecture Series Salts of Terminal Alkynes • Addition of an alkyne anion followed + by H3O gives an α-acetylenic alcohol • Note: this is a 2-C homologation O HC C O - Na+ HC C OH - HC C: Na+ + HCl H2 O Sodium Cyclohexanone A sodium 1-Ethynyl- acetylide alkoxide cyclohexanol Homologation is a term used for extending a carbon chain 171717 Organic Lecture Series Oxidation of Terminal Alkynes O HO CCH3 H2 O ααα H2 SO4, HgSO4 HO C CH An ααα-hydroxyketone O ααα HO CH2CH 1. (sia) BH 2 βββ 2. H2O2, NaOH A βββ-hydroxyaldehyde (these reactions are from O-chem I) 181818 Pg 285: use of (sia) 2BH Organic Lecture Series Addition of HCN • HCN adds to the C=O group of an aldehyde or ketone to give a cyanohydrin • Cyanohydrin: a molecule containing an - OH group and a -CN group bonded to the same carbon O HO C N + HCN C C H3C H H3C H Acetaldehyde 2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin) 191919 Organic Lecture Series Addition of HCN • Mechanism of cyanohydrin formation – Step 1: nucleophilic addition of cyanide to the carbonyl carbon - H3 C H3 C O -• • C OC+ C N H3 C H3 C C N – Step 2: proton transfer from HCN gives the cyanohydrin and regenerates cyanide ion - H C O-H H3 C O 3 -• • C + HCCN + CN H C C N H3 C CN 3 pKa=9.3 202020 Organic Lecture Series Cyanohydrins – catalytic reduction of the cyano group gives a 1°amine OH OH Ni CHC N+ 2H2 CHCH2 NH2 βββ α Benzaldehyde 2-Amino-1-phenylethanol cyanohydrin (racemic) (racemic) βββ−β−−−Phenethylamines 212121 Organic Lecture Series Biosynthesis of Dopamine L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine 222222 Organic Lecture Series βββ−β−−−Phenethylamines (Natural) NH2 HO OH OH NH2 Dopamine HO OH Norepinephrine 232323 Organic Lecture Series βββ−β−−−Phenethylamines (synthetic) H N CH3 CH3 N-methylamphetamine NH2 CH3 amphetamine 242424 Organic Lecture Series Overall Synthetic Transformation of Wittig Reagents & Its Variations R R' O C Ketone Alkenes Can Be or Cyclic Olefins 252525 Organic Lecture Series Wittig Reaction The Wittig reaction is a very versatile synthetic method for the synthesis of alkenes (olefins) from aldehydes and ketones + - O + Ph3 P-CH2 CH2 + Ph3 P=O Cyclohexanone A phosphonium Methylene- Triphenyl- ylide cyclohexane phosphine oxide Ylides are reagents (or reactive intermediates) which have adjacent charges: Ph3P CH2 Ph3P CH2 262626 Phosphonium ylides Organic Lecture Series Phosphonium ylides are formed in two steps: Step 1: nucleophilic displacement of iodine by triphenylphosphine + SN 2 Ph3 P+ CH3 -I Ph3 P-CH3 I Triphenylphosphine Methyltriphenylphosphonium iodide (an alkyltriphenylphosphine salt) Step 2: treatment of the phosphonium salt with a very strong base, most commonly BuLi, NaH, or NaNH 2 + - + - CH3 CH2 CH2 CH2 Li + H-CH2 -PPh3 I Butyllithium + CH CH CH CH + - 3 2 2 3 CH2 -PPh3 + LiI Butane A phosphonium ylide Not exam material 272727 Organic Lecture Series Wittig Reaction Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene Step 1: nucleophilic addition of the ylide to the electrophilic carbonyl carbon O CR2 - :O CR2 O CR2 + - + Ph3 P CH2 Ph3 P CH2 Ph3 P CH2 A betaine An oxaphosphetane Step 2: decomposition of the oxaphosphatane O CR2 Ph P=O + 3 R2 C=CH2 Ph3 P CH2 Triphenylphosphine An alkene 28 oxide 2828 Organic Lecture Series Wittig Reaction O + + Ph P=O Ph3 P 3 Acetone 2-Methyl-2-heptene O + + + Ph P=O Ph Ph3 P Ph Ph 3 H (Z)-1-Phenyl-2- (E)-1-Phenyl-2- Phenyl- butene butene acetaldehyde (87%) (13%) Resonance stabilized Wittig reagent: H O O Ph + Ph3 P Ph O OEt OEt + Ph3 P=O Phenyl- Ethyl (E)-4-phenyl-2-butenoate acetaldehyde (only the E isomer is formed) 292929 Organic Lecture Series Addition Reactions to Carbonyl Compounds Note: Water can be added to ketones & aldehydes. 303030 Organic Lecture Series Addition of H 2O to Carbonyls Addition of water ( hydration ) to the carbonyl group of an aldehyde or ketone gives a geminal diol, commonly referred to a gem- diol – gem-diols are also referred to as hydrates acid or base OH CO + H2 O C OH Carbonyl group A hydrate of an aldehyde (a gem-diol) or ketone 313131 Organic Lecture Series Addition of H 2O to Carbonyls – when formaldehyde ( g) is dissolved in water at 20°C, the carbonyl group is more than 99% hydrated H H OH O + H O 2 OH H H Formaldehyde Formaldehyde hydrate (>99%) – the equilibrium concentration of a hydrated ketone is considerably smaller OH O + H O 2 OH Acetone 2,2-Propanediol (99.9%) (0.1%) 323232 Organic Lecture Series Addition of Alcohols to Carbonyls • Addition of one molecule of alcohol to the C=O group of an aldehyde or ketone gives a hemiacetal • Hemiacetal: a molecule containing an - OH and an -OR or -OAr bonded to the same carbon acid or base OH O + H-OR OR A hemiacetal 333333 Organic Lecture Series Formation of a hemiacetal-- base catalyzed – Step 1: proton transfer from HOR gives an alkoxide fast and reversible Na + -OCH B - + H OR B H + - OR 3 – Step 2: attack of RO - on the carbonyl carbon – O O: – CH3 -C-CH3 + :O-R CH3 -C-CH3 OR – Step 3: proton transfer from the alcohol to O - gives the hemiacetal and generates a new base catalyst O:– OH + - CH3 -C-CH3 + H OR CH3 -C-CH3 OR OR OR 343434 Organic Lecture Series Formation of a hemiacetal -- acid catalyzed Step 1: proton transfer to the carbonyl oxygen + H O fast and O reversible - CH3 -C-CH3 +H-A CH3 -C-CH3 + A Step 2: attack of ROH on the carbonyl carbon + H O O-H