hapter 19 Aldehydes and Ketones: Nucleophilic Addition eactions - aldehyde - substance that has an organic group () bonded to functionality () - ketone methanol catalyst heat - substance that has two organic groups (, ) bonded to functionality ( ) formaldehyde 3 3 2-propanol Zn 380 o 3 3 acetone Naming Aldehydes - aldehydes are named by replacing the terminal -e of the corresponding alkane with -al - the parent chain must contain the - group, with the carbon atom being number as carbon 1 3 23 ethanal propanal 3 3 2 2 3 2-ethyl-4-methylpentanal 1
- for complex aldehydes where the - is attached to a ring, the suffix -carbaldehyde is used cyclohexanecarbaldehyde 2-naphthalenecarbaldehyde Naming Ketones - ketones are named by replacing the terminal -e of the corresponding alkane with -one - parent chain is longest chain that contains ketone group 3 2 2 2 3 3 2 2 3 3 2 2 3 3-hexanone 4-hexen-2-one 2,4-hexanedione - common ketones: 3 3 3 acetone acetophenone benzophenone - - group can be referred to as a substituent - the word acyl is used, with a name ending -yl 3 acyl acetyl formyl benzoyl - doubly bonded oxygen can be referred to as substituent - the prefix oxo- is used 3 2 2 2 3 methyl 3-oxohexanoate 2
Preparation of Aldehydes and Ketones Aldehydes 1) oxidation of primary alcohols using pyridinium chlorochromate 2 P 2 l 2 citronellol citronellal (82%) 2) oxidative cleavage of alkenes with vinylic hydrogen 3 1. 3 2. Zn, 3 3 2 2 2 2 1-methylcyclohexene 6-oxoheptanal (86%) 3) reduction of carboxylic acid derivatives by diisobutylaluminum hydride (DIBA) - + Y - Y 1. DIBA, toluene, -78 o 3 ( 2 ) 10 3 3 ( 2 ) 10 2. 3 + methyl dodecanoate dodecanal (88%) where DIBA = ( 3 ) 2 2 Al 2 ( 3 ) 2 Ketones - methods are analogous to aldehydes 1) oxidation of secondary alcohols (variety of oxidizing agents) ( 3 ) P ( 3) 2 l 2 4-tert-butylcyclohexanol 4-tert-butylcyclohexanone (90%) 2) ozonolysis of alkenes (unsaturated carbon must be disubstituted) 2 1. 3 3 2. Zn/ 3 + 3 3
3) Friedel-rafts acylation of an aromatic ring with an acid chloride + 3 l All 3 heat 3 benzene acetyl chloride acetophenone (95%) 4) hydration of terminal alkynes in presence of g 2+ catalyst 3 + 3 ( 2 ) 3 3 ( 2 ) 3 3 gs 4 1-hexyne 2-hexanone (78%) 5) nucleophilic attack of carboxylic acid derivatives 3 ( 2 ) 4 l + - ( 3 ) 2 uli + 3 ( 2 ) 4 3 hexanoyl chloride dimethyl copper lithium 2-heptanone (81%) xidation of Aldehydes and Ketones [] no hydrogen ' aldehyde carboxylic acid ketone - aldehydes are readily oxidized to yield carboxylic acids 3 ( 2 ) 4 r 3, 3 + acetone, 0 o 3 ( 2 ) 4 hexanal hexanoic acid (85%) - oxidizing agents: KMn 4, hot N 3, r 3 (most common) 4
Tollens eagent - a solution of silver oxide (Ag 2 ) in aqueous ammonia - oxidizes aldehydes in high yield without harming carbon-carbon double bonds or other functional groups in the molecule benzaldehyde Ag 2 N 4, 2, ethanol benzoic acid - oxidations occur through intermediate 1,1-diols, or hydrates 2 r 3 3 + aldehyde hydrate carboxylic acid - formed by reversible nucleophilic addition of water Ketones - ketones are inert to most oxidizing agents, but undergo a slow cleavage reaction when treated with hot alkaline KMn 4 1. KMn 4, 2, Na 2. 3 + cyclohexanone hexanedioic acid (79%) - best used for symmetrical ketones, since unsymmetrical ketones give mixtures of products 5
Nucleophilic Addition eactions of Aldehydes and Ketones - most general reaction of aldehydes and ketones - nucleophile attacks the electrophilic = carbon atom from approximately 45 o to the plane of the carbonyl group Three General Steps 1) rehybridization of the carbonyl carbon from sp 2 to sp 3 occurs 2) an electron pair from the carbon-oxygen double bond moves toward the electronegative oxygen atom 3) a tetrahedral alkoxide ion intermediate is produced The Nucleophile - can be either negatively charged (:Nu - ) or neutral (:Nu); if neutral, usually carries a hydrogen atom that can be eliminated negatively charged nucleophiles 3 N neutral nucleophiles 3N N2 6
elative eactivity of Aldehydes and Ketones - aldehydes are generally more reactive in nucleophilic reactions for both steric and electronic reasons - sterically, the transition state is less crowded in an aldehyde - electronically, aldehydes are more reactive because of the greater polarization of aldehyde carbonyl groups ' ' 1 o carbocation (less stable, more reactive) 2 o carbocation (more stable, less reactive) aldehyde (less stable δ+, more reactive) ketone (more stable δ+, less reactive) 7
- additionally, aromatic aldehydes are less reactive in nucleophilic addition reactions than aliphatic aldehydes - electron-donating resonance effect of the aromatic ring makes the carbonyl group less electrophilic than the carbonyl group of an aliphatic aldehyde Addition of 2 : ydration - aldehydes and ketones react with water to yield 1,1-diols, or geminal (gem) diols 3 3 3 3 acetone (99.9%) acetone hydrate (0.1%) - the reaction is reversible, the position of the equilibrium depending upon the structure of the carbonyl compound: - the equilibrium generally favors the less crowded compound for steric reasons - for instance, aqueous solution of formaldehyde consists of 99.9% gem diol and 0.1% aldehyde, whereas an aqueous solution of acetone consists of only 0.1% gem diol and 99.9% ketone + 2 formaldehyde (0.1%) formaldehyde hydrate (99.9 %) - the nucleophilic addition reaction is slow in pure water; however, the reaction is catalyzed by both acid and base + Y ' Y ' favored when: Y = - 3, -, -Br, -l, S - 4 8
Base-atalyzed Addition Acid-atalyzed Addition Mechanism Addition of N: yanohydrin Formation - aldehydes and unhindered ketones react with N to yield cyanohydrins (() N) N N benzaldehyde mandelonitrile (88%) - cyanohydrin formation is reversible and base-catalyzed - reaction occurs rapidly when a small amount of base or KN is added to generate the nucleophile 9
Mechanism N N N N + N benzaldehyde tetrahedral intermediate madelonitrile (88%) - a rare example of addition of a protic acid (Y) to a carbonyl group Further hemistry 1. LiAl 4, TF, 2 N 2 2. 2 N N 2-amino-1-phenylethanol benzaldehyde madelonitrile 3 + mandelic acid Addition of Grignard eagents: Alcohol Formation - treatment of a ketone or aldehyde with MgX gives an alcohol by way of nucleophilic addition involving a carbanion = 1) MgX 2) 2 2 () - acid-base complexation of Mg 2+ with the carbonyl oxygen atom makes the carbonyl group a better acceptor - nucleophilic addition of : - then produces a tetrahedral magnesium alkoxide intermediate - protonation yields the alcohol, the nucleophilic attack being irreversible 10
Mechanism Addition of ydride eagents: Alcohol Formation - treatment of a ketone or aldehyde with LiAl 4 or NaB 4 yields an alcohol = 1) LiAl 4 2) 3 + 2 () - the carbonyl group is reduced upon addition of an hydride ion and work-up with aqueous acid or water 11
Addition of Amines: Enamine Formation N N 2 ketone or aldehyde 2 N N imine enamine - both reactions are typical examples of nucleophilic addition reactions in which water is eliminated from a tetrahedral intermediate and a new =Nu bond is formed Mechanism of Imine Formation - imine formation displays a p dependency such that the reaction is slow in the presence of too much acid or too much base - a p of 4.5 represents the most optimized p for reaction to occur p 12
Application of Imines - reagents such as hydroxylamine and 2,4-dinitrophenylhydrazine react with ketones and aldehydes to form oximes and 2,4-dinitrophenylhydrazones, respectively + N 2 N + 2 cyclohexanone hydroxylamine cyclohexanone oxime (mp 90 o ) + 3 3 acetone N 2N N 2 N 2 2,4-dinitrophenylhydrazine N 2 N N 3 3 N 2 acetone 2,4-dinitrophenylhydrazone (mp 126 o ) - such products are highly crystalline and can be used to purify and characterize liquid ketones and aldehydes Mechanism of Enamine Formation Addition of ydrazine: Wolff-Kishner eaction - valuable method for converting a ketone or aldehyde into an alkane, 2 = 2 2, known as the Wolff-Kishner reaction 2 3 2 NN 2 2 3 + N 2 + 2 K propiophenone propylbenzene (82%) 2 NN 2 K 3 + N 2 + 2 cyclopropanecarbaldehyde methylcyclopropane (72%) 13
Wolff-Kishner eaction Mechanism Addition of Alcohols: Acetal Formation - ketone or aldehyde reacts reversibly with two equivalents of an alcohol in the presence of acid to yield an acetal, 2 ( ) 2 ' acid + 2 + 2 catalyst ' ketone/aldehyde acetal - under acidic conditions, the carbonyl is reactive to attack of alcohol δ- δ+ A neutral carbonyl protonated carbonyl - the initial product is a hydroxy ether or hemiacetal, which then leads to E1-like loss of water and formation of an oxonium ion 3 + catalyst 3 + catalyst 3 3 3 cyclohexanone hemiacetal cyclohexaone dimethyl acetal - all reactions are reversible such that the reaction can be driven forward or backward depending upon the reaction conditions - forward reaction: removal of 2 - backward reaction: addition of excess acid 14
Acid-atalyzed Acetal Formation Acetals as Protecting Groups - acetals can be used as protecting groups for aldehydes and ketones 3 2 2 2 3 ethyl 4-oxopentanoate 2 2 + catalyst 2 2 3 2 2 2 3 cannot be done directly 1) LiAl 4 2) 3 + 2 2 + 3 2 2 2 3 + 2 2 3 2 2 2 - in practice it is useful to use ethylene glycol as a protecting group Addition of Phosphorus Ylides: The Wittig eaction - ketone or aldehyde can be converted into an alkene using a phosphorus ylide or phosphorane, 2 - -P + ( 6 5 ) 3 2 = 2 - -P + ( 6 5 ) 3 2 = 2 + (Ph) 3 P= - the reaction produces a dipolar intermediate referred to as a betaine, which decomposes to yield an alkene and triphenylphosphine oxide, (Ph) 3 P= - reaction is extremely general, leading to mono-, di-, and trisubstituted alkenes (tetrasubstituted cannot be prepared) 15
Preparation of the Phosphorus Ylide triphenylphosphine S P + N 2 BuLi 3 Br P 3 P 2 Br TF bromomethane - methyltriphenylphosphonium bromide methyltriphenylphosphorane Mechanism of the Wittig eaction - Wittig reaction always replaces = with = with no side products, which makes the reaction extremely valuable in synthetic chemistry 1) 3 MgBr 3 2 2) Pl 3 1-methylcyclohexene methylenecyclohexane 9:1 ratio cyclohexanone + - ( 6 5 )P- 2 TF solvent 2 + ( 6 5 )P methylenecyclohexane (84%) 16
Application of the Wittig eaction + P(Ph) 3 retinal retinylidenetriphenylphosphorane Wittig reaction β-carotene The annizzaro eaction - involves the nucleophilic addition of - to an aldehyde to give a carboxylic acid and an alcohol 1) - + 2) 3) 3 + - a tetrahedral intermediate expels hydride ion as a leaving group, which is accepted by a second aldehyde molecule tetrahedral intermediate 1) 2) 3 + + benzoic acid (oxidized) benzyl alcohol (reduced) - the aldehyde that undergoes the substitution of - by - is oxidized, while the molecule that undergoes the addition of - is reduced; reaction is therefore a disproportionation reaction 17
- the annizzaro reaction is very limited and is therefore not particularly useful synthetically, having few applications - the reaction, however, serves as a useful model for reactions in living organisms that involve reduced nicotinamide adenine dinucleotide (NAD) as a reducing agent N 2 N 2 N 2 P P N 2 N N N reduced nicotinamide adenine dinucleotide (NAD) Mechanism of NAD eduction '' 2 N N + ' ketone 2 N N + ' alcohol NAD NAD + onjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones - conjugate addition (or 1,4-addition) involves addition of a nucleophile to the = double bond of an α,β-unsaturated aldehyde or ketone 1) :Nu - α β 2) 3 + Nu - electrophilic site of α,β-unsaturated aldehyde or ketone is β carbon which is, effectively, activated by the carbonyl group δ- α δ+ β 18
onjugate Addition of Amines - primary and secondary amines add to α,β-unsaturated aldehydes and ketones to give β-amino aldehyes and ketones 3 2 + N(23)2 ethanol 3 2 2 N( 2 3 ) 2 3-buten-2-one diethylamine 4-N,N-diethylamino-2-butanone (92%) 2-cyclohexenone + ethanol 3 N 2 methylamine N 3 3-(N-methylamino)cyclohexanone - reaction conditions are mild and conjugate addition predominates onjugate Addition of Alkyl Groups: rganocopper eactions - lithium diorganocopper reagents (: - ) (Gilman reagents) facilitate conjugate additions to aldehydes and not ketones 2) 3 + 1) : - : - - = u - primary, secondary, and tertiary alkyl groups, as well as aryl and alkenyl groups, undergo the addition reaction; alkynyl groups react poorly 19
Examples: 1) Li( 2 =) 2 u, ether 2) 3 + 2-cyclohexenone 3-vinylcyclohexanone (65%) 1) Li( 6 5 ) 2 u, ether 2) 3 + 2-cyclohexenone 3-phenylcyclohexanone (70%) Gilman eagents vs. Grignard eagents 1) 3 MgBr, ether or 3 Li 2) 3 + 3 1-methyl-2-cyclohexen-1-ol (95%) 2-cyclohexenone 1) Li( 3 ) 2 u, ether 2) 3 + 3 3-methylcyclohexanone (97%) - regiochemistry is controlled by the selection of the reagent Postulated Mechanism Li + ( 2 u) - u + u 3 + - addition product is thought to form through a u-containing intermediate that involves transfer of an group and elimination of a neutral organocopper species, u 20
Biological Nucleophilic Addition eactions 1) Pathway to amino acids in bacteria N N reducing 2 3 + N 2 3 3 enzyme pyruvic acid imine alanine 2) Defense mechanism of the millipede N enzyme + N (poisonous) mandelonitrile Spectroscopy of Aldehydes and Ketones Infrared Spectroscopy - strong = bond absorption from 1660 to 1770 cm -1 - position of absorption is sensitive to nature of carbonyl group - saturated aldehydes: near 1730 cm -1 - aromatic aldehydes: near 1705 cm -1 - saturated ketones: near 1715 cm -1 - aromatic ketones: near 1685 cm -1 - aldehydes show - absorptions from 2720 to 2820 cm -1 Infrared Spectrum of Benzaldehyde 21
Infrared Spectrum of yclohexanone NM Spectroscopy - aldehyde protons () absorb near 10 δ in 1 NM spectrum - hydrogen atoms next to carbonyl are slightly deshielded and absorb near 2.0 2.3 δ - carbonyl group of aldehydes and ketones show 13 NM resonances in the range 190 215 δ 3 136.5 192 211 31 200 134 130,129 25 27 42 1 Spectrum of Acetaldehyde 22
Mass Spectrometry - aliphatic aldehydes and ketones that have hydrogens on their gamma (γ) carbon atoms undergo a cleavage known as a McLafferty rearrangement ' γ 2 β 2 α + McLafferty rearrangement ' 2 + 2 + - aldehydes and ketones also undergo a so-called α-cleavage + alpha cleavage 2 + 2 ' rearrangement ' + Mass Spectrum of 5-Methyl-2-hexanone Notes 23
Notes 24