CH 8. Aldehydes, Ketones & Condensations

A. Carbonyl Structure and Reactivity

1. Structure, naming and preparation

a. Carbonyl bonding, geometry and electrophilicity

• C=O contains one σ bond and one π bond. Its carbon is approximately sp²-hybridized and trigonal planar. Polarization toward oxygen leaves carbon partially positive and electrophilic; nucleophilic addition makes it tetrahedral.

• An aldehyde has at least one H on its carbonyl carbon; a ketone has two carbon substituents. Aldehydes are commonly less hindered and more reactive toward addition than comparable ketones.

• Lower electron donation as well as lower steric crowding contributes to the greater addition reactivity of many aldehydes.

• Related acyl derivatives, such as carboxylic acids and esters, commonly undergo nucleophilic acyl substitution rather than the simple addition characteristic of aldehydes and ketones.

b. Naming aldehydes

• Replace the terminal -e of the parent alkane with -al for an acyclic aldehyde; the aldehyde carbon is carbon 1.
• When –CHO is directly attached to a ring, the suffix -carbaldehyde is often used.

c. Naming ketones

• Use -one for the ketone suffix and number the longest appropriate chain to give the carbonyl carbon a low locant.
• A carbonyl group written as a substituent is commonly designated by oxo-.

d. Alcohol oxidation

• Primary alcohols can be oxidized to aldehydes with suitable mild conditions, such as PCC; stronger aqueous oxidation can continue to carboxylic acids.
• Secondary alcohols are oxidized to ketones.
• Tertiary alcohols lack an ordinary carbinol hydrogen and do not undergo comparable simple oxidation without C–C bond cleavage.

e. Alternative sources of carbonyl groups

• Acid-catalyzed hydration of a terminal alkyne generally gives a methyl ketone after enol–ketone tautomerization; ethyne gives ethanal.
• Friedel–Crafts acylation can form aryl ketones from aromatic substrates under suitable conditions.

• Alkene cleavage is another route to carbonyl compounds. A formyl group can be named as a substituent when a higher-priority functional group controls the suffix.

B. Nucleophilic Addition

1. Acidic and basic addition pathways

a. Basic or nucleophilic conditions

• A nucleophile supplies an electron pair to the electrophilic carbonyl carbon.
• The carbonyl π electrons move toward oxygen as a tetrahedral alkoxide intermediate forms.
• Protonation converts the alkoxide to an alcohol.
• Aldehydes are often more reactive than structurally comparable ketones because steric crowding and electron donation are generally lower.

• Hydride, organometallic carbon and cyanide provide different nucleophiles; in each case the new bond forms to carbonyl carbon rather than oxygen.

b. Acid-catalyzed addition

• Protonation of carbonyl oxygen increases electrophilicity at the carbonyl carbon.
• A neutral nucleophile, such as water or an alcohol, may then attack; deprotonation gives the addition product.
• The acid-catalyzed and basic pathways are distinct and must not be drawn using the wrong protonation states.

• Strongly basic organometallic reagents are incompatible with aqueous acid during addition; introduce acid only in a separate workup.

c. Carbonyl hydrate

• Water adds reversibly across the C=O group to give a geminal diol (two –OH groups on the same carbon).
• Hydration can be accelerated by acid or base; the equilibrium position depends strongly on substrate substitution and electron-withdrawing effects.
• Formaldehyde and some strongly electron-poor aldehydes have relatively favorable hydration equilibria compared with typical ketones.

d. Cyanohydrin formation

• Cyanide can add to a carbonyl group, and protonation gives a cyanohydrin containing –OH and –CN on the same carbon.
• Cyanohydrin formation creates a new C–C bond; the new alcohol-bearing carbon may become stereogenic.

• Formation is reversible and depends on substrate and conditions. Later nitrile hydrolysis can give a carboxylic acid; include the carbon introduced by CN in the product carbon count.

C. Grignard and Hydride Addition

1. Carbon–carbon bonds and reduction products

a. NaBH₄ and LiAlH₄

• NaBH₄ commonly reduces aldehydes to primary alcohols and ketones to secondary alcohols.
• LiAlH₄ also reduces aldehydes and ketones; it is stronger and requires careful anhydrous handling followed by workup.
• Hydride adds to the carbonyl carbon, then workup protonates the alkoxide.

Transformation	Typical outcome
Aldehyde + NaBH₄	Primary alcohol
Ketone + NaBH₄	Secondary alcohol
Aldehyde + RMgX / workup	Secondary alcohol (formaldehyde → primary)
Ketone + RMgX / workup	Tertiary alcohol
Carbonyl + H₂O	Hydrate (geminal diol)
Carbonyl + 2 ROH / H⁺	Acetal / ketal + water

b. Grignard addition to carbonyl carbon

• Organomagnesium reagents (RMgX) behave as strongly nucleophilic carbon reagents.
• Addition to an aldehyde other than formaldehyde gives a secondary alcohol after aqueous or acidic workup; addition to a ketone gives a tertiary alcohol.
• Formaldehyde gives a primary alcohol after organomagnesium addition and workup.
• Grignard reagents are destroyed by water, alcohols, carboxylic acids, and other sufficiently acidic protons.

• Count the carbon atoms contributed by the incoming organometallic group.

• Organolithium reagents (RLi), like Grignard reagents, can make a new C–C bond and give an alcohol after protonation under compatible conditions.

c. Facial attack and stereochemical outcomes

• A planar achiral carbonyl can be attacked on either face. In an achiral environment, creating one new stereocenter commonly gives a racemic product.

d. Wittig alkene formation

• A phosphorus ylide replaces a carbonyl O with a carbon fragment to form C=C, with phosphine oxide as a byproduct.
• Disconnect the target alkene across its C=C to identify a carbonyl partner and the ylide carbon. E/Z selectivity depends on ylide type and conditions.

e. Carbonyl to methylene

• Clemmensen reduction uses strongly acidic Zn(Hg)/HCl conditions; Wolff–Kishner reduction uses hydrazine and strong base with heat. Both can remove carbonyl oxygen to give CH₂.
• Choose conditions compatible with the substrate. A thioacetal followed by suitable desulfurization is another carbonyl-to-methylene strategy noted in the source.

Transformation	Typical method
C=O → C–OH	NaBH₄ or LiAlH₄; workup
C=O → C=C	Wittig reagent
C=O → CH₂, acidic	Zn(Hg), HCl
C=O → CH₂, basic	NH₂NH₂, base, heat

f. Selective acyl chemistry

• An acid chloride can be reduced selectively to an aldehyde with a suitable bulky hydride, or converted to a ketone with an organocuprate. Nitrile addition by an organometallic reagent gives a ketone after hydrolysis.
• Ordinary Grignard addition to an ester usually proceeds beyond the ketone intermediate; a ketone synthesis requires a reagent/substrate combination that stops after the intended carbon addition.

g. Dithiane strategy

• A 1,3-dithiane can act as a protected carbonyl and, after deprotonation at the carbon between sulfur atoms, as an acyl-anion equivalent. Alkylation at that carbon followed by appropriate hydrolytic deprotection reveals a carbonyl.
• This umpolung reverses the usual electrophilic role of carbonyl carbon. It is distinct from desulfurization, which removes sulfur to produce a methylene group.

D. Acetals and Imines

1. Reversible addition and condensation

a. Hemiacetal formation

• One equivalent of an alcohol may add to an aldehyde or ketone, producing a hemiacetal or hemiketal bearing both –OH and –OR on one carbon.
• Hemiacetals are important intermediates in acetal formation and occur in cyclic sugars.

b. Acetal formation

• Acid-catalyzed reaction with alcohol can yield an acetal, containing two –OR groups on the former carbonyl carbon.
• Excess alcohol or removal of water shifts the equilibrium toward acetal formation; aqueous acid promotes hydrolysis back to the carbonyl compound.
• Acetals can protect a carbonyl group during selected synthetic transformations.

• The acetal center no longer contains a C=O bond.

• Suitable diols can form cyclic acetals.

c. Protecting-group logic

• Acetals generally tolerate many basic nucleophilic conditions but hydrolyze under aqueous acid. They can protect a carbonyl during an incompatible step.
• Protection and deprotection add steps and must be compatible with the other functional groups in the molecule.

d. Condensation

• A primary amine can form an imine after addition, proton transfer and loss of water. Mild acid catalysis is useful, while strong acid can suppress nucleophilicity by protonating the amine.
• A secondary amine can form an enamine when the carbonyl partner has an appropriate α-H. The product contains a C=C adjacent to N.

• Imine formation proceeds through a carbinolamine intermediate before loss of water.

e. Related derivatives

• Hydroxylamine forms oximes; hydrazine derivatives form hydrazones. These are condensation products rather than simple alcohol products.
• Reductive amination reduces an imine/iminium intermediate to an amine and is developed with nitrogen chemistry.

E. Enolates and Aldol Reactions

1. Tautomerism, alpha chemistry and carbon–carbon formation

a. Interconversion

• A carbonyl compound with an alpha hydrogen may interconvert with its enol tautomer.
• Keto and enol tautomers differ in proton location and double-bond placement; they are distinct structures, not resonance contributors.
• For many simple aldehydes and ketones, the keto form is favored at equilibrium.

b. Acid- and base-mediated pathways

• Acid catalysis involves carbonyl oxygen protonation followed by removal of an alpha proton.
• Base catalysis involves alpha deprotonation to an enolate followed by protonation at oxygen to produce an enol.

c. Enolate stabilization

• An enolate delocalizes negative charge between α-carbon and oxygen. Reactions at either site can occur depending on electrophile and conditions.
• Typical ketone α-H atoms are much more acidic than alkane H atoms. A β-dicarbonyl compound is more acidic still because its conjugate base can interact with two carbonyl groups.

Acidic site	Typical approximate pKa
β-Diketone central C–H	about 9
β-Keto ester central C–H	about 11
Ketone α-C–H	about 19–21
Ester α-C–H	about 25

• Enolate resonance contributors retain atom connectivity while delocalizing charge between oxygen and the α-carbon.

d. Enolate alkylation at the alpha carbon

• A carbon-centered enolate can react with a suitable primary alkyl halide in an SN2 process.
• The reaction forms a new C–C bond at the alpha position.
• Steric hindrance and competing elimination can limit reactions with secondary or tertiary electrophiles.

• A sufficiently strong base is needed to generate an enolate; a relatively nonnucleophilic base such as LDA is useful for substantial deprotonation under controlled conditions.

e. Regioselectivity

• An unsymmetrical carbonyl can form different enolates. Kinetic versus thermodynamic enolate selection depends on base, temperature, solvent and equilibration.
• Repeated alkylation and competing O-alkylation can occur. Plan both the selected α-site and the electrophile, rather than treating all enolates as interchangeable.

f. Acid versus base

• Acidic conditions often give controlled monohalogenation through the enol. Under basic conditions, each installed halogen can increase the acidity of remaining α-H atoms and encourage further halogenation.
• For carboxylic acids with an α-H, Hell–Volhard–Zelinsky conditions enable α-halogenation through an activated acyl intermediate, followed by hydrolysis.

g. Haloform reaction

• A methyl ketone can undergo exhaustive α-halogenation and cleavage under suitable X₂/OH⁻ conditions to yield carboxylate and CHX₃.
• The iodoform reaction can also be positive for alcohols oxidized under the conditions to suitable methyl ketones, as well as ethanol/acetaldehyde. Product interpretation depends on the starting functional group.

h. Addition step

• An enolate adds to another aldehyde or ketone. Protonation gives a β-hydroxy carbonyl product: the electrophile carbonyl becomes OH while the donor carbonyl remains.
• The donor needs an enolizable α-site; the acceptor must have an accessible electrophilic carbonyl.

• An enol-derived carbon nucleophile can also participate under suitable conditions; trace the new bond from the donor α-carbon to the acceptor carbonyl carbon.

i. Dehydration

• On heating or under suitable acid/base conditions, a beta-hydroxy carbonyl compound can lose water.
• The resulting alpha,beta-unsaturated carbonyl system is conjugated.
• Aldol addition and aldol condensation are different stages; dehydration is not automatic in every experiment.

• Under basic conditions, suitable aldol dehydration commonly follows an E1cb-type sequence.

j. Selectivity

• When two different enolizable carbonyl partners are mixed, multiple aldol products may be possible.
• A carbonyl partner lacking alpha hydrogens, such as benzaldehyde, cannot serve as a normal enolate donor.
• Preforming a specific enolate can improve selectivity.

k. Ring formation

• A molecule containing two suitably spaced carbonyl groups may undergo intramolecular aldol chemistry.
• Formation of common five- or six-membered rings is often favored when accessible.

l. 1,2 versus 1,4

• An α,β-unsaturated carbonyl has electrophilic sites at carbonyl carbon and β-carbon. Direct 1,2-addition attacks C=O; conjugate 1,4-addition attacks β-carbon.
• Stabilized carbon nucleophiles, such as many β-dicarbonyl enolates, commonly participate in Michael addition.

m. Product connectivity

• After conjugate attack and proton transfer, the acceptor carbonyl is retained. A carbonyl-containing donor can produce a 1,5-dicarbonyl relationship.
• A synthesis plan should track the new donor-α to acceptor-β bond and account for every carbon before choosing reagents.