Chemistry · Organic chemistry · Year 3

Carbonyl compounds and synthesis

How are the smells of banana, cinnamon and vanilla synthesised in a flask?

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The situation

In a food-flavouring and perfume workshop, the banana smell comes from isoamyl acetate, cinnamon from cinnamaldehyde, vanilla from vanillin and almond from benzaldehyde; every one of them contains a carbonyl group C=O. In one flask a technologist makes “banana essence” from ethanoic acid and isoamyl alcohol; in another, yellow crystals form from benzaldehyde and acetone; in a third, a new C–C bond is built from a Grignard reagent in dry ether. Why does an ester never form completely from equal amounts of acid and alcohol, why does even one drop of water ruin a Grignard reagent, and why does acetone not give a silver mirror?

Topic

Carbonyl compounds, carboxylic acids and organometallic synthesis. Perfume and food flavouring workshop: cinnamaldehyde, vanillin, fruity-smelling esters (isoamyl acetate — banana). In the laboratory, benzaldehyde and acetone…

Key ideas

• Nucleophilic addition and keto–enol tautomerism
• Aldol reaction and esters
• Grignard reagent and cross-coupling

Formulas

Nucleophilic addition: a tetrahedral alkoxide, then protonation.

Esterification equilibrium (ethanoic acid + ethanol): at 1 : 1, $x^2/{(1-x)}^2=4$, i.e. $x=2/3$.

Keto–enol tautomerism. Meyer's method: $n(\mathrm{Br}{}_2)=cV=n(\text{enol})$, enol fraction $=cVM/m$.

Grignard reagent + CO₂ → benzoic acid (a new C–C bond).

Aldol addition and crotonic condensation.

Theory

The carbonyl group: structure, nomenclature, preparation

The carbonyl carbon is sp²: the C=O group is planar, the angles are ≈ 120°, and the bond length is 121 pm. Oxygen is more electronegative, so C=O is polar: the carbon is δ+ (electrophilic) and the oxygen is δ− (basic); the dipole moment of acetone is ≈ 2.9 D. The empty π* orbital is on the carbon — a nucleophile approaches it at an angle of ≈ 107° to the C=O bond (the Bürgi–Dunitz angle). Aldehydes RCHO (named with “-al”: methanal, ethanal, benzaldehyde) and ketones R₂CO (“-one”: propanone — acetone, butanone, acetophenone); saturated, unsaturated (acrolein, cinnamaldehyde), aromatic and dicarbonyl compounds. Aldehydes are more reactive than ketones: they have one alkyl group fewer — the carbon is more positive and more exposed. Ways of making the carbonyl group: oxidation of alcohols (primary → aldehyde, secondary → ketone) and dehydrogenation over copper; hydration of alkynes (Kucherov: ethanal from acetylene, ketones from its homologues; via hydroboration, vinylboranes → aldehydes); ozonolysis of alkenes or the Wacker process ($2\mathrm{CH}{}_2=\mathrm{CH}{}_2+\mathrm{O}{}_2\stackrel{\stackrel{}{\mathrm{PdCl}{}_2,\mathrm{CuCl}{}_2}}{\to }2\mathrm{CH}{}_3\mathrm{CHO}$); catalytic oxidation of alkanes with air (cyclohexane → cyclohexanol and cyclohexanone); aromatic ketones — Friedel–Crafts acylation; the cumene process (phenol and acetone); hydrolysis of gem-dihalides; a Grignard reagent with nitriles. Radical chain reactions of alkanes (halogenation, sulfochlorination, sulfoxidation, Konovalov nitration; and in superacids, electrophilic substitution — Olah), electrophilic addition to alkenes (Markovnikov's rule, the Kharasch peroxide effect), allylic halogenation (NBS, or Cl₂ at high temperature), addition of HX to alkynes and the Kucherov reaction are covered in the “Radical and electrophilic mechanisms” experiment; here they appear as sources of carbonyl compounds. Nucleophilic addition to alkynes also occurs: alcohols (vinyl ethers), ethanoic acid (vinyl acetate), HCN (acrylonitrile). In the IR spectrum C=O is at ≈ 1715 cm⁻¹ (ketone), ≈ 1725 (aldehyde), ≈ 1735 (ester) — see “Spectra: determining structure”. School level — “Phenol, aldehydes and ketones”.

Nucleophilic addition and keto–enol tautomerism

The nucleophile adds to the C=O carbon, the π electrons shift to oxygen — a tetrahedral alkoxide, which is then protonated. Strong nucleophiles (H⁻ — NaBH₄, LiAlH₄; R⁻ — Grignard; CN⁻) add directly; weak ones (H₂O, ROH, amines) add under acid catalysis (C=O is protonated and the carbon is activated). Water gives hydrates $\mathrm{R}{}_2\mathrm{C}(\mathrm{OH}){}_2$: the equilibrium depends on electronic and steric factors (on the board); chloral hydrate is a stable solid. Alcohols give hemiacetals and acetals (H⁺ catalysis; an acetal is stable in base — a way of protecting a carbonyl); formaldehyde polymerises — polyacetals (paraformaldehyde, trioxane, polyformaldehyde — an engineering plastic). HCN gives cyanohydrins (base catalysis); a planar carbonyl is attacked equally likely from both sides, so a chiral product is a racemate. NaHSO₃ gives bisulfite adducts (aldehydes and methyl ketones). Nitrogen nucleophiles: primary amines give imines (Schiff bases), secondary amines give enamines, hydroxylamine gives oximes, hydrazines give hydrazones (2,4-dinitrophenylhydrazones are yellow to orange precipitates, a qualitative test for carbonyls); the reaction goes through a carbinolamine, loss of water requires acid, but in a very acidic medium the amine is protonated — so the rate is greatest at pH ≈ 4–5 (L27). Keto–enol tautomerism: a carbonyl compound with an α-H is in equilibrium with its enol form (catalysed by acid or base, via the enolate). In simple ketones there is very little enol (a few parts per billion in acetone), but in β-dicarbonyl compounds the enol is stabilised by conjugation and an internal hydrogen bond: ethyl acetoacetate is ≈ 8 % enol as a liquid, ≈ 0.4 % in water and ≈ 46 % in hexane — a non-polar solvent favours the internally H-bonded enol. Qualitative tests (L10): FeCl₃ gives a violet-red colour; bromine water removes the colour (Br₂ adds to the C=C bond of the enol), then the keto form is enolised again and the colour returns. Meyer's method: rapid bromine titration at 0 °C — $n(\mathrm{Br}{}_2)=n(\text{enol})$; because the keto → enol change is slow, the titration is done quickly.

Aldol–crotonic condensation, the Reformatsky reaction, heterofunctional compounds

Base catalysis: OH⁻ removes an α-H → an enolate (a C-nucleophile) → adds to another carbonyl to give an alkoxide → protonated to the aldol (β-hydroxycarbonyl). On heating, especially if conjugation helps, the aldol loses water — crotonic condensation (E1cB: via the enolate, OH⁻ leaves) — an α,β-unsaturated carbonyl. Acid catalysis: the carbonyl is protonated, and the enol (a weaker nucleophile) attacks the protonated carbonyl (a strong electrophile); water is lost by the E1 route. Claisen–Schmidt (mixed aldol): benzaldehyde, which has no α-H, acts only as the electrophile — with acetone it gives benzalacetone, with excess benzaldehyde dibenzalacetone (yellow crystals); the Perkin reaction — benzaldehyde + acetic anhydride + CH₃COONa → cinnamic acid; phenolphthalein — phthalic anhydride + 2 phenol (H₂SO₄); pentaerythritol — acetaldehyde + 4 formaldehyde (three aldol additions and a crossed Cannizzaro). The Cannizzaro reaction: aldehydes without α-H disproportionate in concentrated alkali into an alcohol and the salt of a carboxylic acid. The Reformatsky reaction: α-bromo ester + Zn → a zinc enolate (milder than a Grignard reagent — it does not attack the ester group) → adds to an aldehyde or ketone and, after hydrolysis, gives a β-hydroxy ester, and from it a β-hydroxy acid. Heterofunctional compounds: hydroxy acids — lactic (sour milk), malic (apple), citric (lemon), tartaric (grape), salicylic acid (from salicin glycoside in willow bark); on heating, α-hydroxy acids give lactides, β- give unsaturated acids, γ- and δ- give lactones. Aldehydo- and keto acids — glyoxylic acid, pyruvic acid CH₃COCOOH, acetoacetic acid (easily decarboxylated: acetone + CO₂ — ketone bodies). Amino acids are internal salts (details in the topic on peptides).

Carboxylic acids and their derivatives

Structure: the carboxyl group –COOH; the acidity (ethanoic acid pKa 4.76) arises because in the carboxylate ion the negative charge is shared equally between two oxygens (both C–O bonds 127 pm); acceptor groups increase acidity (ClCH₂COOH 2.9; CCl₃COOH 0.7). Kinds: saturated (formic, acetic, propionic, butyric, palmitic, stearic), unsaturated (acrylic, oleic), aromatic (benzoic), dibasic (oxalic, malonic, adipic, phthalic, terephthalic). Naming: “-oic acid” (ethanoic, butanoic). Preparation: oxidation of primary alcohols and aldehydes, alkylbenzenes with KMnO₄ (benzoic acid), hydrolysis of nitriles, Grignard reagent + CO₂, malonic ester synthesis; in industry, carbonylation of methanol (ethanoic acid) and oxidation of p-xylene in air (terephthalic acid). Derivatives and their reactivity: acyl chloride > anhydride > ester ≈ acid > amide > carboxylate — the weaker a base the leaving group is, and the less it donates electrons to C=O by resonance, the more reactive the compound (the IR frequency of C=O also falls in about this order: ≈ 1800 → 1580 cm⁻¹; an anhydride has two lines, 1820 and 1760). Nucleophilic substitution at an sp² carbon (acyl substitution) is addition–elimination: the nucleophile forms a tetrahedral intermediate, then the leaving group departs; it is easy to go from a more reactive derivative to a less reactive one (acyl chloride + NH₃ → amide; aniline + acetic anhydride → acetanilide). Esterification (Fischer): acid-catalysed, reversible, K ≈ 4 (ethanoic acid + ethanol); to raise the yield Le Chatelier's principle is used — the amount of one of the substances at equilibrium is changed. An experiment with ¹⁸O-labelled alcohol: the ¹⁸O stays in the ester — the OH group of the acid is lost (the acyl C–O bond is broken). Hydrolysis: acidic — reversible; alkaline (saponification) — irreversible: the acid formed at once turns into the resonance-stabilised carboxylate ion, which does not react with the alcohol again. Natural sources: vinegar (fermented wine), formic acid (ants, nettles), butyric acid (butter), fatty acids (fats and oils), esters — the smell of fruits and flowers (isoamyl acetate — banana, ethyl butanoate — pineapple). School level — “Acids, esters and soap”.

Organometallic compounds and cross-coupling

Organomagnesium compounds (V. Grignard, 1900): $\mathrm{RX}+\mathrm{Mg}\stackrel{\stackrel{}{\mathrm{ether}}}{\to }\mathrm{RMgX}$ — in dry ether or THF (the ether oxygen solvates the magnesium); an iodine crystal starts the reaction. The C–Mg bond is polar: the carbon is δ− — a strong nucleophile and base: water, alcohol and acid destroy it at once ($\mathrm{RMgX}+\mathrm{H}{}_2\mathrm{O}\stackrel{}{\to }\mathrm{RH}+\mathrm{Mg}(\mathrm{OH})\mathrm{X}$), so the glassware is dried and a CaCl₂ tube protects the mixture from moisture in the air. Reactions: CO₂ → carboxylic acids; HCHO → primary alcohols, other aldehydes → secondary alcohols, ketones → tertiary alcohols; esters → tertiary alcohols (the intermediate ketone is more reactive than the ester); nitriles → ketones; epoxides → alcohols. Organolithium compounds RLi ($\mathrm{RX}+2\mathrm{Li}\stackrel{}{\to }\mathrm{RLi}+\mathrm{LiX}$) are even more reactive. Organocopper — Gilman cuprates R₂CuLi: the Corey–House synthesis with haloalkanes (R–R′), 1,4-addition to α,β-unsaturated ketones. Organozinc — the Reformatsky reagent, the Simmons–Smith reaction (cyclopropanation), Negishi coupling. Organopalladium — cross-coupling: Pd(0) catalyst, oxidative addition (Ar–X), transmetallation (Suzuki — ArB(OH)₂, Negishi — ArZnX, Kumada — ArMgX, Sonogashira — alkyne + Cu), reductive elimination (Ar–Ar′); the Heck reaction — aryl halide + alkene + base: via syn-migratory insertion and β-hydride elimination (the cycle on the board); Tsuji–Trost — allylation through palladium π-allyl complexes. The 2010 Nobel Prize went to R. Heck, E. Negishi and A. Suzuki. Alkene metathesis is also organometallic catalysis (details in “Radical and electrophilic mechanisms”). Wurtz reaction: $2\mathrm{RX}+2\mathrm{Na}\stackrel{}{\to }\mathrm{R}-\mathrm{R}+2\mathrm{NaX}$ (n-octane, bibenzyl).

Redox; the laboratory, safety and the model

Oxidation: aldehydes are oxidised easily — Tollens' reagent (silver mirror), Fehling's solution (red Cu₂O; aromatic aldehydes hardly react with Fehling's), KMnO₄, K₂Cr₂O₇; ketones are oxidised with difficulty (with a strong oxidant with C–C cleavage: cyclohexanone → adipic acid). Side chains: toluene → benzoic acid (KMnO₄), p-xylene → terephthalic acid, anthracene → anthraquinone (CrO₃). Alkenes: KMnO₄ (cold — diol, hot — cleavage), ozonolysis → carbonyl compounds. Reduction: NaBH₄ (aldehydes and ketones → alcohols), LiAlH₄ (esters and acids too), catalytic hydrogenation (H₂/Ni, Pt — heterogeneous; homogeneous — Wilkinson's catalyst), Clemmensen (Zn(Hg) + HCl) and Wolff–Kishner (N₂H₄, KOH): C=O → CH₂; Cannizzaro — disproportionation. Laboratory work: L9 — esters and acetanilide; L10 — the enol test, benzalacetone, dibenzalacetone, cinnamic acid, phenolphthalein, pentaerythritol; L11 — n-octane, bibenzyl, benzoic acid, benzhydrol, triphenylcarbinol; L12 — benzoic, terephthalic and adipic acids, acetone, anthraquinone, benzaldehyde, cyclohexanol; L27 — imines, oximes, hydrazones. Safety: diethyl ether is very flammable and builds up peroxides in storage — use an electric heater, not a naked flame; sodium and Grignard reagents react violently with water; bromine is toxic and burns (fume cupboard, gloves); HCN and cyanides are extremely toxic — cyanohydrin synthesis only in a specialised laboratory; chromium(VI) compounds are carcinogenic; oxidation with concentrated HNO₃ releases NO₂; safety goggles are compulsory; never smell or taste reagents. Model: the hydration and enol fractions are approximate literature values (they depend on temperature and concentration); the keto → enol rate, the rate constants of esterification and aldol, the Grignard yield (92 %) and the moisture losses are model values; K = 4 is used for all primary alcohols; “removing water” is a general model of shifting an equilibrium (in practice for ethyl acetate it is not water but the ester itself that is distilled off as it forms — L9); the pH dependence of the rate of imine formation is qualitative; the molecules are schematic (1 Å ≈ 4.5 cm), and laboratory time is speeded up.

Did you know?

• Organomagnesium compounds were discovered in 1900 in Lyon by Victor Grignard; for this work he received the 1912 Nobel Prize in Chemistry together with Paul Sabatier.
• Isoamyl acetate, with its banana smell, is a danger signal of honeybees — a component of the sting pheromone: the scent released when one bee stings calls the others to attack.

Inside the experiment

The experiment starts from a real-life situation: you predict the result, change the controls, run the experiment and draw a conclusion. Inside are missions, theory, a quiz and a guided tour in which the camera moves and explains the key points.

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