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)
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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:
Ph3PCH2 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
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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
CH3 -C-CH3 + H-O-R CH3 -C-CH3 O+ H R Step 3: proton transfer from the oxonium ion to A - gives the hemiacetal and generates a new acid catalyst
OH OH
CH3 -C-CH3 CH3 -C-CH3 + H-A + O OR A - H R 353535
Organic Lecture Series Addition of Alcohols to Carbonyls • Hemiacetals react with alcohols to form acetals Acetal: a molecule containing two -OR or -OAr groups bonded to the same carbon
+ OH H OR + H-OR + H2O OR OR A hemiacetal acetal
Nota Bene : acetals are STABLE in base 363636 Organic Lecture Series Begin Mechanism from the hemiacetal stage: Step 1: proton transfer from HA gives an oxonium ion
H + H HO O - R-C-OCH3 + HA R-C-OCH3 + A: H H An oxonium ion
Step 2: loss of water gives a resonance- stabilized cation + H H O + + R-C OCH R-C OCH + H O R-C OCH3 3 3 2 H H H A resonance-stabilized cation 373737
Organic Lecture Series
Step 3 : reaction of the cation (an electrophile) with methanol (a nucleophile) gives the conjugate acid of the acetal + H CH3 + O CH3 -OH + R-C OCH3 R-C OCH3 H H A protonated acetal
Step 4 : proton transfer to A - gives the acetal and generates a new acid catalyst + H CH3 O OCH3 - (4) A: + R-C OCH3 R-C-OCH3 + H-A H H An acetal 383838 Organic Lecture Series Addition of Alcohols to Carbonyls – with ethylene glycol and other glycols, the product is a five-membered cyclic acetal – this a method of “protecting” ketones + O + HO H + O OH H2 O O Cyclic acetal
393939
Organic Lecture Series Dean-Stark Trap
404040 Organic Lecture Series Acetals as Protecting Groups • How to bring about a Grignard reaction between these compounds:
O OH O O H Br ?? H + H
Benzaldehyde 4-Bromobutanal 5-Hydroxy-5-phenylpentanal (racemic)
O This Grignard cannot be made!! BrMg H 414141
Organic Lecture Series Acetals as Protecting Groups • a Grignard reagent prepared from 4- bromobutanal will self-destruct ( decompose ). – first protect the -CHO group as an acetal: O + O H Br OH Br + H2 O H + HO O A cyclic acetal – then prepare the Grignard reagent:
O-MgBr+ O O 1. Mg, ether Br O O 2. C6 H5 CHO A chiral magnesium alkoxide (produced as a racemic mixture) – hydrolysis (not shown) gives the target molecule 424242 Organic Lecture Series Addition of Nitrogen Nucleophiles • Ammonia, 1°aliphatic amines, and 1°aromatic amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases) • Water is removed by Dean-Stark trap or chemical dehydration (e.g. molecular sieves)
O + H CH3 CH + H2 N CH3 CH=N + H2 O Acetaldehyde Aniline An imine (a Schiff base)
+ H O + NH3 NH + H2 O Cyclohexanone Ammonia An imine (a Schiff base) 434343
Organic Lecture Series Addition of Nitrogen Nucleophiles – a value of imines is that the carbon-nitrogen double bond can be reduced to a carbon- nitrogen single bond
H+ O + H2N -H2 O Cyclohexanone Cyclohexylamine
H H / Ni NN2
(An imine) Dicyclohexylamine
Does not have to isolated 444444 Organic Lecture Series Addition of Nitrogen Nucleophiles • Secondary amines react with the C=O group of aldehydes and ketones to form enamines (alk en e and amine )
+ H OH-N+ NH+ 2 O Cyclohexanone Piperidine An enamine (a secondary amine) – the mechanism of enamine formation involves formation of a tetrahedral carbonyl addition compound followed by its acid-catalyzed dehydration
454545
Organic Lecture Series Acidity of ααα-Hydrogens
Hydrogens alpha to a carbonyl group are more acidic than hydrogens of other hydrocarbons (e.g. alkanes, alkenes, aromatic). O H H α α H H
464646 Organic Lecture Series + - H A + H 2 O H 3 O + A + - [H 3 O ] [A ] K e q = Note: l and s are [H A ] [H 2 O] not used in K [H O + ] [A -] 3 Freshman [H 2 O ] K e q = [H A ] Flashback!!
+ - [H 3 O ] [A ] K = a [H A ] 474747
Organic Lecture Series Acidity of ααα-Hydrogens
Hydrogens alpha to a Type of Bond pKa carbonyl group are more 16 acidic than hydrogens of CH3 CH2O-H alkanes, alkenes, and O alkynes but less acidic 20 than the hydroxyl CH3 CCH2-H hydrogen of alcohols CH3C C-H 25 CH2 =CH-H 44 CH3 CH2-H 51 pKa = -log Ka 484848 Organic Lecture Series
ααα-Hydrogens are more acidic because the enolate anion is stabilized by : 1. delocalization of its negative charge (resonance effect) 2. the electron-withdrawing inductive effect of the adjacent electronegative oxygen
- O O O - CH3 -C-CH2 -H + :A CH3 -C CH2 CH3 -C=CH2 + H-A Resonance-stabilized enolate anion
494949
Organic Lecture Series Keto-Enol Tautomerism – protonation of the enolate anion on oxygen gives the enol form* ; protonation on carbon gives the keto form
O O- - CH3 -C-CH2 CH3 - C= CH2 Enolate anion H-A H-A O OH - - A + CH3 -C-CH3 CH3 - C= CH2 + A Keto form Enol form
*Enol: made from 2 functional groups-alk en e and alcoh ol 505050 Organic Lecture Series Keto-Enol Tautomerism – acid-catalyzed equilibration of keto and enol tautomers occurs in two steps Step 1: proton transfer to the carbonyl oxygen
• • + H O fast and O reversible - CH3 -C-CH3 + H-A CH3 -C-CH3 + A Keto form The conjugate acid of the ketone
Step 2: proton transfer to the base A - + H O OH slow - CH3 -C-CH2 -H + :A CH3 -C=CH2 + H-A
Enol form 515151
Organic Lecture Series Keto-Enol Tautomerism
Keto-enol % Enol at equilibria Keto form Enol form Equilibrium for simple O OH -5 aldehydes CH3 CH CH2 = CH 6 x 10 O OH and -7 CH3 CCH3 CH3 C= CH2 6 x 10 ketones lie O OH far toward 1 x 10 -6 the keto O OH -5 form 4 x 10
525252 O O Organic Lecture Series Carboxylic Acids & E ste rs C C R OH R OR'
O O
C C K e ton e s & A ld e h y d e s Oxidation R H R R' OH
C A lc o h o ls R R' H H
C Hydrocarbon (lowest oxidation) R R' H 535353
Organic Lecture Series Oxidation from O-Chem I
545454 Organic Lecture Series Oxidation of Aldehydes Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents, including
*H 2CrO 4
CHO H2 CrO4 COOH Hexanal Hexanoic acid
555555 + - * See 10.8 for Jones reagent & PCC : pyridine •ClCrO 3
Organic Lecture Series Oxidation of Aldehydes
• They are also oxidized by Ag(I) – in one method, a solution of the aldehyde in aqueous ethanol or THF is shaken with a slurry of silver oxide
O O CH O COH CH3 O CH 3 T HF, H2 O HCl + Ag2 O + Ag HO NaOH H2 O HO Vanillin Vanillic acid
565656 Organic Lecture Series Oxidation of Aldehydes
Aldehydes are oxidized by O 2 in a radical chain reaction – liquid aldehydes are so sensitive to air that
they must be stored under N 2
OO
2 CH + O2 2 COH
Benzaldehyde Benzoic acid 575757
Organic Lecture Series Reduction – aldehydes can be reduced to 1°alcohols – ketones can be reduced to 2°alcohols – the C=O group of an aldehyde or ketone can
be reduced to a -CH 2- group
Can Be Can Be Aldehydes Reduced to Ketones Reduced to OH OO RCH2 OH RCHR' RCH RCR'
RCH3 RCH2 R'
585858 Organic Lecture Series Metal Hydride Reduction The most common laboratory reagents for the
reduction of aldehydes and ketones are NaBH 4 and LiAlH 4 - – both reagents are sources of hydride ion, H: a very powerful nucleophile
H H
+ + H A l H L i H B H N a H Hydride H H
Lithium Aluminum Hydride Sodium Borohydride LAH NaBH 4 595959
Organic Lecture Series Sodium Borohydride Reduction
– reductions with NaBH 4 are most commonly carried out in aqueous methanol , in pure methanol, or in ethanol
– one mole of NaBH 4 reduces four moles of aldehyde or ketone O methanol 4RCH + NaBH4
- + H2 O ( RCH2 O) 4 B Na 4RCH2 OH + borate A tetraalkyl borate salts
606060 Organic Lecture Series Sodium Borohydride Reduction • The key step in metal hydride reduction is transfer of a hydride ion to the C=O group to form a tetrahedral carbonyl addition compound This H comes from water during hydrolysis
+ H O O BH3 Na O-H + H2 O Na H-B-H + R-C-R' R-C-R' R-C-R' H H H This H comes from the hydride reducing agent
Not exam material 616161
Organic Lecture Series LAH Reduction
– unlike NaBH 4, LiAlH 4 reacts violently with water, methanol , and other protic solvents – reductions using it are carried out in dry (anhydrous) diethyl ether or tetrahydrofuran (THF)
O OH ether - + H2 O 4RCR + LiAlH (R CHO) Al Li 4RCHR + aluminum 4 2 4 H+ or OH- A tetraalkyl salts aluminate 626262 Organic Lecture Series Catalytic Reduction • Catalytic reductions are generally carried
out at from 25°to 100°C and 1 to 5 atm H 2
O OH Pt + H 2 25 oC, 2 atm Cyclohexanone Cyclohexanol
O 2 H2 H N i OH trans- 2-Butenal 1-Butanol (Crotonaldehyde)
Note: Both the olefin and the carbonyl are reduced 636363
Organic Lecture Series
646464 Organic Lecture Series Catalytic Reduction • A carbon-carbon double bond may also be reduced under these conditions: O 2 H2 H Ni OH trans-2-Butenal 1-Butanol (Crotonaldehyde) – by careful choice of experimental conditions, it is often possible to selectively reduce a carbon-carbon double in the presence of an aldehyde or ketone O OH 1. NaBH RCH=CHCR'4 RCH=CHCHR' 2. H2 O O O Rh RCH=CHCR'+ H2 RCH2 CH2 CR' 656565
Organic Lecture Series Clemmensen Reduction
– refluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene group – Classic reaction but harsh conditions limit its use
OH O OH Zn(Hg), HCl
666666 Organic Lecture Series Wolff-Kishner Reduction – in the original procedure, the aldehyde or ketone and hydrazine are refluxed with KOH in a high-boiling solvent – the same reaction can be brought about using hydrazine and potassium tert-butoxide in DMSO (Di- methyl sulfoxide)
O + KOH H2 NNH2 diethylene glycol Hydrazine (reflux)
+ + N2 H2 O 676767
Organic Lecture Series Racemization • Racemization at an α-carbon may be catalyzed by either acid or base • Once stereochemistry is set, this is usually an undesirable side reaction.
O OH O
Ph Ph Ph (R)-3-Phenyl-2- An achiral (S)-3-Phenyl-2- butanone enol butanone
686868 Organic Lecture Series ααα-Halogenation α-Halogenation: aldehydes and ketones with at least one α-hydrogen react at an α- carbon with Br 2 and Cl 2 O O Br
+ Br2 + HBr CH3COOH Acetophenone ααα-Bromo- acetophenone – reaction is catalyzed by both acid and base – Caution!! These are lachrymators
696969
Organic Lecture Series ααα-Halogenation Organic Lecture Series • Acid-catalyzed α-halogenation Step 1: acid-catalyzed enolization- forms the enol O H H-O R slow R'-C-C-R CC R R' R Step 2: nucleophilic attack of the enol on halogen
H-O R H O Br fast - C C + Br Br CC R + Br: R' R' R R
Step 3: (not shown) proton transfer to solvent completes the reaction
707070 Organic Lecture Series ααα-Halogenation • Base-promoted α-halogenation Step 1: formation of an enolate anion
- OH O O: slow - R R - •• R'-C-C-R + :OH CC CC + H2 O R R' R R' R Resonance-stabilized enolate anion
Step 2: nucleophilic attack of the enolate anion on halogen - O: R O Br fast CC + Br BrCC R + Br R' R R' R 717171
Organic Lecture Series ααα-Halogenation Organic Lecture Series • Acid-catalyzed ααα-halogenation: – introduction of a second halogen is slower than the first – introduction of the electronegative halogen on the α- carbon decreases the basicity of the carbonyl oxygen toward protonation • Base-promoted ααα-halogenation: – each successive halogenation is more rapid than the previous one – the introduction of the electronegative halogen on the α-carbon increases the acidity of the remaining α- hydrogens and, thus, each successive α-hydrogen is removed more rapidly than the previous one
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