Ch 19- Aldehydes & Ketones

What are the 2 categories of carbonyl compounds?

1. aldehydes & ketones

2. carboxylic acids & derivatives

What kinds of reactions do Aldehydes & ketones undergo?

nucleophilic addition, H/R isn’t a good leaving group

What kinds of reactions do carboxylic acids & derivatives undergo?

nucleophilic substitution, R can be a good leaving group

What is the nature of a carbonyl?

• O is electrophile, 2 lone pairs of electrons, partial negative

• C is nucleophile, 3 sigma bonds & 1 pi = sp2, partial positive

• shape = trigonal planar

• bond angle around C = 120

• polarized w/ partial charges

Reactions Seen by Carbonyls

• nucleophilic addition

• nucleophilic acyl substitutions

• alpha substitutions

• carbonyl condensations

Aldehyde Nomenclature

• aldehydes = replace terminal -e of alkane name with -al

• parent chain must have CHO, CHO =C1

• CHO on ring = carbaldehyde

• CHO is substituent on chain = formyl

Ketone Nomenclature

• replace terminal -e of alkane with one

• parent chain is longest one containing ketone

• numbering starts at end closes to carbonyl C

• substituent = prefix oxo

Unsystematic Names for Ketones/Aldehydes

R-C=O as a substituent = acyl group, used w/ suffix -yl from root of carboxylic acid

Preparing Aldehydes

1. Oxidize 1o alcohols w/ pyridinium chlorochromate/PCC (CH2OH → CHO)

2. oxidative cleave w/ ozone for alkenes w/ vinylic H

3. reduce ester w/ DIBAH (C-COOCH3 → CHO)

Preparing Ketones

1. oxidize 2o alcohol, many reagents possible

2. ozonolysis of alkenes (only if 1/both of unsaturated C atoms is disubstituted)

3. friedel-crafts acylation of aromatic ring w/ acid chloride, presence of AlCl3 catalyst

4. hydration of terminal alkynes in presence of Hg, makes methyl ketone

Oxidation of Aldehydes

1 H can be oxidized ONCE to a carboxylic acid

Oxidation of Ketones

0 H so can’t oxidize, can still get a -COOH group, no H directly attached

Aldehydes

• CrO3 in aq acid (Jones’ Reagent) oxidizes aldehydes to carboxylic acids

• Silver oxide/Ag2O in aq ammonia (Tollens’ reagent) oxidizes aldehydes (no acid)

Hydrates & Aldehydes

• aldehyde oxidations occur through 1,1-diols/hydrates

• aldehyde hydrate oxidized to carboxylic acid by usual reagents for alcohols

In Aldehyde oxidations, is adding water to the carbonyl group possible? Can it be reversed

Addition is possible, and reversible

Ketones making COOH

• slow cleavage with/ hot alkaline KMnO4

  • C-C bond next to C=O broken to give carboxylic acids

• only good for symmetrical ketones, unsymmetrical gives mixture of products

Nucleophile

electron rich species reacting w/ electron poor species (C=O)

• (-) → OH-, H-, R3C-, RO-, N///C-

• neutral → H2O, ROH, H3N, H2NR, H will be elim

Addition

implies 2 systems combine to give a single entity

How do nucleophilic addition reactions work?

• nuc approaches 75o to the plane of C=O & adds to C

• tetrahedral alkoxide ion intermediate produced

• 2 possible products!

  • protonation = make alcohol

  • carbonyl O elim as OH/H2O to give C=nuc

Aldehyde NAS

base catalyzed, strong nucleophile, anionic

• nuc adds directly to C=O to make intermediate alkoxide, alkoxide is protonate on workup w/ dilute acid

• nucs = RMgX, LiAlH4, NaBH4, Wittig Rxn [(Ph)3P+:CRH-]

Ketone NAS

acid catalyzed, weak nucleophile, neutral

• C=O needs to be activated before nuc attack

• nucs = H2O, ROH, RNH2

• protonating carbonyl = structure redrawn in another resonance form, reveals electrophilic character of C since it’s a carbocation

Which is more reactive, aldehydes or ketones?

aldehydes, electronic & steric

• steric = transition state for addition is less crowded, lower in energy for A, only H on it & 1 R group, ketone has 2 R groups, more things in the way, aldehydes have 1 large substituent on C=O, ketones have 2

• electronic = less stabilization of partial positive, more reactive, ketone is more stabilized/less reactive through more alkyl groups stabilizing C=O’s C inductively

• more alkyl groups stabilize + character

• aldehyde C=O is more polarized than ketone C=O

• aromatic aldehydes < aliphatic aldehydes (more reactive), e- donating resonance effect of ring makes C=O less reactive electrophile than carbonyl group of aliphatic aldehyde

Oxygen Nucleophiles

1. addition of water/hydration

2. addition of alcohols: acetal formation

3. addition of HCN: cyanohydrin formation

Hydration

• makes 1,1 diols or germinal diols/hydrates, 2 OH groups on 1 C

• hydrates not stable enough to be isolated, equilibrium shifts back to starting materials except for a few simple aldehydes

• hydrates are the reactive species in the [O] of aldehydes to acids

• reversible process, slow in pure water, catalyzed by A/B

  • B → nuc is OH-, stronger nuc than water

• reaction of C=O w/ H-Y (Y= EN-) gives addition product/adduct, reversible formation

Acetal Formation

• nuc add then nuc sub

• reversible

• add 1 eq of alcohol = hemiacetal/hemiketal (ac=aldehyde, ket=ketone)

• add 2 eq of alcohol = acetal/ketal

  • 1,1-germinal diethers

• catalyzed only by acidic conditions

• acetals → used in carbs, also protecting groups

• equilibrium shifted to acetal → excess use of alcohol or removing water as it forms

• can use 1,2 or 1,3 diols to make cyclic acetals

• stable to strong bases & nucleophiles

• acetals can be converted to aldehyde/ketone by heating w/ aqueous acid

Cyanohydrin Formation

• H-C///N (H cyanide) is toxic, reacts slowly

• small amount of base added → N///C- nuc made, base catalyzed addition (also use KC///N, NaC///N)

• react to make cyanohydrins RCH(OH)C///N

  • add CN to C=O makes tetrahedral intermediate, which is protonated

  • equilibrium favors adduct

• reactivity: formaldehyde > other aldehydes > ketones

• ketones hindered by large alkyl groups react slowly, give poor % yields

• useful as precursors

  • reduced by LiAlH4 to give 1o amines (RCH2NH2)

  • hydrolyzed by hot aqu

Nuc Addition of Grignard & Hydride Reagents

• treat aldehyde/ketone w/ grig reagent = alcohol

• nuc add of eq of carbanion, C-Mg is polarized, so reacts practically (R-, MgX+)

• irreversible, carbanion is a poor leaving group

What happens when a grignard reagent is added to aldehydes/ketones?

• alcohols are made

• Formaldehyde (H2C=O) → 1o alcohol

• Aldehydes (RCHO) → 2o alcohol

• Ketones (RR’CO) → 3o alcohol

Hydride Addition/Reduction

• 2 H atoms added across C=O to give H-C-O-H

• LiAlH4 & NaBH4 = donors of hydride ion

  • rxn usually in Et2O or THF followed by H3O+ workups

• protonation after addition yields alcohol

• aldehyde = 1o alcohol

• ketone = 2o alcohol

Forming Imines & Enamines: Primary Amines

• reaction type → nuc addition then elim

• primary amines, R-NH2, or ArNH2 give carbinolamines

  • dehydrate to give substituted imines

• rxn done in acidic buffer (pH 4.4) to activate C=O, help dehydration w/o inhibiting nucelophile

• VERY acidic/basic = VERY slow rxn

Forming Imines & Enamines: Secondary Amines

• reaction type → nuc addition then elim

• R2NH gives carbinolamines, dehydrate to give enamines

• enamines = alkene amines

• carbinolamine can only elim to give C=C since no N-H in carbinolamine

Why do carbinolamines only give C=C with eliminating?

• no N-H in carbinolamine

• need slightly acidic so carbinolamine o can be protonated to become a good leaving group (H2O)

• too acidic =amine becomes protonated, rxn can’t occur

Mechanism of Forming Imines

• primary amine adds to C=O

  • proton lost from N, adds to O → carbinolamine

  • protonate OH → convert to water as leaving group

  • result = iminium ion, loses proton

  • acid required for loss of OH, too much acid blocks RNH2, why the acidic buffer is there, reaction goes but it’s not too much

Carbinolamine

neutral amino alcohol

Imine Derivatives

• adding amines w/ atom containing LP on adjacent atom, occurs readily, gives stable imines

• hydroxylamine (NH2OH) → makes oximes

• 2,4-dinitrophenylhydrazine → 2,4-dinitrophenylhydrazones

• semicarbazide (NH2NH CONHS)

Mechanism of Formation of Enamine

• starts off same as imine formation

• after adding R2NH, proton is lost from adjacent C

Wittig Reaction

• nucleophilic addition of phosphorous ylides

• nuc add then elim

• C=O → C=C

• phosphorous ylide adds to aldehyde/ketone → betaine

• betaine decomposes through ring → alkene & triphenylphosphine oxide [(Ph)3P=O]

• = made at location of og aldehyde/ketone

• NO ALKENE ISOMERS MADE (only E/Z)

Betaine

dipolar intermediate in Wittig Reaction, formed when a phosphonium ylide reacts with a carbonyl compound.

For which alkenes can the Wittig Reaction be used for?

monosub, disub, & trisubstituted alkenes, makes pure alkene

NO TETRA = too sterically hindered

Planning a Wittig

• divide target mol at C=C bond

• ½ becomes ketone/aldehyde, other is ylide

• ylide need to be unhindered, so is 1o