Organic Synthesis: Reagents, Coupling Reactions, Named Reactions, Strategy, Enolates and Asymmetric Synthesis
1. Mg, Li, Cu, B, Zn, P, S, Sn and Si reagents
| Element | Reagent type | Characteristic use |
|---|---|---|
| Mg | Grignard reagents RMgX | add to aldehydes and ketones (2° and 3° alcohols), twice to esters (3° alcohols), to CO₂ (acids), to nitriles (ketones after hydrolysis) |
| Li | RLi, LDA, LiHMDS | more reactive carbanions; LDA as a hindered, non-nucleophilic base for kinetic enolates |
| Cu | Gilman cuprates R₂CuLi | 1,4-addition to enones, S_N2 on alkyl halides and epoxides, acid chloride → ketone without over-addition |
| B | boranes, boronic acids, boron enolates | hydroboration, Suzuki coupling, syn-selective aldols |
| Zn | Reformatsky, Simmons–Smith, organozincs | β-hydroxy esters from α-bromo esters; CH₂I₂/Zn(Cu) cyclopropanation (stereospecific); Negishi coupling |
| P | phosphonium ylides, phosphonates | Wittig: non-stabilised ylides give mainly Z-alkenes, stabilised ones E; Horner–Wadsworth–Emmons gives E-enoates |
| S | sulfur ylides, 1,3-dithianes, sulfones | Corey–Chaykovsky epoxides (sulfonium) and cyclopropanes from enones (sulfoxonium); dithiane acyl-anion equivalents; Julia olefination |
| Sn | organostannanes, Bu₃SnH | Stille coupling; radical dehalogenation, Barton–McCombie deoxygenation, radical cyclisation |
| Si | silyl ethers, allylsilanes, silyl enol ethers | protecting groups (TMS, TBS, TIPS); Sakurai allylation; Mukaiyama aldol; Peterson olefination; Hiyama coupling |
Two principles connect these. Polarity: a carbon bonded to an electropositive metal is nucleophilic, and the more ionic the C–M bond (Li > Mg > Zn > Cu > B, Sn, Si), the more reactive and less selective the reagent. Silicon’s special effects: a C–Si bond stabilises a positive charge on the β-carbon (the β-silicon effect, by σC–Si → p overlap), which directs electrophiles to the γ-carbon of allylsilanes; silicon also forms very strong bonds to O and F, which drives Peterson elimination, Brook rearrangement and fluoride-promoted desilylation.
2. Palladium-catalysed couplings, metathesis and McMurry coupling
The cross-couplings share one catalytic cycle: oxidative addition of an aryl, vinyl or allyl halide (or triflate) to Pd(0), transmetallation of the second organic group from a main-group metal to palladium, and reductive elimination to form the new C–C bond and regenerate Pd(0). They differ in the nucleophilic partner. The Heck reaction instead couples the halide with an alkene: after oxidative addition the alkene inserts into Pd–C and β-hydride elimination releases the substituted alkene (usually E), with base regenerating Pd(0) — there is no transmetallation.
| Reaction | Nucleophilic partner | Notes |
|---|---|---|
| Suzuki | organoboron R–B(OH)₂ + base | base forms a borate that transmetallates; non-toxic, air-stable reagents |
| Stille | organostannane R–SnBu₃ | tolerant of most functional groups; tin residues are toxic |
| Sonogashira | terminal alkyne + CuI + amine | copper acetylide transmetallates; gives aryl- and enynes |
| Negishi | organozinc R–ZnX | very reactive, couples sp³ partners well |
| Kumada | Grignard R–MgX (Ni or Pd) | the first cross-coupling; limited by Grignard reactivity |
| Hiyama | organosilane + F⁻ activator | fluoride makes a pentacoordinate silicate that transmetallates |
| Tsuji–Trost | soft nucleophile (malonate) on an allylic acetate | via an η³-allyl Pd(II); two inversions give overall retention |
| Buchwald–Hartwig | amine + strong base, bulky phosphine | forms aryl C–N bonds (arylamines) |
Olefin metathesis (Grubbs Ru or Schrock Mo carbenes, through metallacyclobutanes) closes rings (RCM, releasing ethylene from a diene), opens strained rings (ROMP) and exchanges alkene partners (cross metathesis). McMurry coupling joins two ketones or aldehydes into an alkene with low-valent titanium (TiCl₃ or TiCl₄ reduced by Zn, LiAlH₄ or Zn–Cu): single-electron transfer gives ketyl radicals that couple to a titanium pinacolate, which is then deoxygenated by the oxophilic titanium; intramolecular versions make medium and large rings.
3. Baylis–Hillman, Henry, Ritter, Sakurai, Tebbe, Pauson–Khand and Nazarov reactions
- Morita–Baylis–Hillman: an activated alkene (acrylate, acrylonitrile, enone) and an aldehyde combine under a nucleophilic tertiary amine (DABCO) or phosphine catalyst to give an α-methylene-β-hydroxy carbonyl compound. The catalyst adds 1,4, the zwitterionic enolate attacks the aldehyde, and elimination releases the catalyst — atom-economical but slow.
- Henry (nitroaldol): a nitroalkane, deprotonated by base, adds to an aldehyde or ketone to give a β-nitro alcohol, which can be dehydrated to a nitroalkene or reduced to a β-amino alcohol.
- Ritter: a carbocation generated in strong acid from a tertiary alcohol or alkene is captured by the nitrogen of a nitrile; the nitrilium ion is hydrated to an N-alkyl amide, e.g. t-BuOH + CH₃CN → N-tert-butylacetamide.
- Hosomi–Sakurai: an allylsilane adds to an aldehyde, ketone or acetal activated by a Lewis acid (TiCl₄) at its γ-carbon; the β-silyl cation formed loses the silyl group, delivering a homoallylic alcohol with the double bond shifted.
- Tebbe olefination: the Tebbe reagent, Cp₂Ti(μ-Cl)(μ-CH₂)AlMe₂, releases the Schrock carbene Cp₂Ti=CH₂, which converts C=O into C=CH₂ through an oxatitanacyclobutane. Unlike the Wittig reagent it methylenates esters and lactones (to enol ethers) and does not epimerise sensitive α-stereocentres.
- Pauson–Khand: an alkyne, an alkene and CO combine on Co₂(CO)₈ to give a cyclopentenone — a formal [2 + 2 + 1] cycloaddition making three new C–C bonds; intramolecular versions build bicyclic rings.
- Nazarov cyclisation: a divinyl ketone, activated by a protic or Lewis acid, forms a pentadienyl cation that undergoes a thermal 4π conrotatory electrocyclisation to an oxyallyl cation; elimination gives a cyclopentenone.
4. Retrosynthesis, umpolung, green chemistry, selectivity and protecting groups
Retrosynthetic analysis works backwards from the target by disconnections — imagined bond cleavages that correspond to known reactions — giving idealised fragments, synthons, which are then matched to real reagents, the synthetic equivalents. Good disconnections are made at bonds next to functional groups, create symmetry or simplify rings, and follow the natural polarity of the molecule: a C–C bond α to a carbonyl disconnects into an enolate (nucleophilic synthon) and an alkyl halide (electrophilic synthon); a 1,3-dioxygenated pattern suggests an aldol, a 1,5-dicarbonyl a Michael addition, a cyclohexenone a Robinson annulation, a cyclohexene a Diels–Alder reaction.
Umpolung (polarity inversion) makes a normally electrophilic carbon nucleophilic. The carbonyl carbon is electrophilic, so an acyl anion (RC⁻=O) or formyl anion is an "unnatural" synthon. Its synthetic equivalents: the 1,3-dithiane of an aldehyde, deprotonated by BuLi at C2 and alkylated, then hydrolysed with Hg²⁺ to the ketone (Corey–Seebach); cyanohydrin anions and the cyanide/thiazolium catalysis of the benzoin reaction; nitroalkane anions followed by the Nef reaction; and lithiated vinyl ethers. Atom economy = (molar mass of the desired product)/(sum of molar masses of all reactants) × 100%: rearrangements, additions and Diels–Alder reactions reach 100%, while Wittig reactions waste a heavy Ph₃PO. It is one of the twelve principles of green chemistry, with catalysis over stoichiometric reagents, safer solvents, and the E-factor (kg waste per kg product) as a measure.
Selectivity: chemoselectivity (NaBH₄ reduces a ketone but not an ester in the same molecule), regioselectivity (hydroboration puts boron on the less substituted carbon), stereoselectivity (diastereo- and enantioselectivity). When selectivity cannot be achieved, a group is protected. The ideal protecting group goes on and comes off in high yield under conditions that leave everything else alone, and a set that is removed under mutually exclusive conditions is orthogonal.
| Group protected | Protecting group | Removed by |
|---|---|---|
| alcohol | TBS (tert-butyldimethylsilyl) ether | F⁻ (TBAF) or acid |
| alcohol | benzyl ether | H₂, Pd/C (hydrogenolysis) |
| alcohol | THP or MOM acetal | aqueous acid |
| aldehyde, ketone | 1,3-dioxolane (ethylene glycol, H⁺) | aqueous acid; stable to base, hydrides and organometallics |
| amine | Boc (tert-butoxycarbonyl) | acid (TFA) |
| amine | Cbz (benzyloxycarbonyl) | H₂, Pd/C |
| amine | Fmoc (fluorenylmethoxycarbonyl) | base (piperidine) |
| carboxylic acid | methyl, tert-butyl, benzyl esters | base hydrolysis, acid, hydrogenolysis respectively |
5. Enolates (including boron enolates), enamines and silyl enol ethers
Enolates are ambident nucleophiles that usually react at carbon with carbon electrophiles. An unsymmetrical ketone gives two: LDA in THF at −78 °C removes the more accessible proton fast and irreversibly, forming the less substituted kinetic enolate; a weaker base in a protic solvent at higher temperature (NaOEt, KOt-Bu) allows equilibration to the more substituted thermodynamic enolate. Enolates are alkylated (S_N2 on primary halides), add to aldehydes (the aldol reaction, giving β-hydroxy carbonyls that may dehydrate by E1cB), acylate esters (the Claisen condensation, driven by deprotonation of the β-keto ester product), add 1,4 to enones (Michael), and in sequence Michael + intramolecular aldol form a cyclohexenone (Robinson annulation).
Aldol stereochemistry is set in a chair-like six-membered transition state (Zimmerman–Traxler) in which the metal bridges the enolate oxygen and the aldehyde oxygen and the aldehyde substituent sits pseudo-equatorial: Z-enolates give syn aldols and E-enolates anti aldols. Boron enolates, with short B–O bonds that tighten the transition state, show this most cleanly: Bu₂BOTf with i-Pr₂NEt gives Z-enolates and syn products with high selectivity. Enamines (from a ketone and a secondary amine such as pyrrolidine) are neutral enolate equivalents that alkylate and acylate at carbon without polyalkylation and are hydrolysed back to the ketone (the Stork enamine reaction). Silyl enol ethers, formed with R₃SiCl and base, are isolable enol equivalents; with a Lewis acid (TiCl₄) they add to aldehydes (the Mukaiyama aldol) and to enones (Mukaiyama–Michael), and they are halogenated or oxidised regioselectively.
6. Stereoselective C=O addition and asymmetric synthesis
A nucleophile adding to a carbonyl next to a stereocentre (M = medium, L = large, S = small substituents) prefers one diastereotopic face. Cram’s rule placed the large group anti to the carbonyl oxygen; the modern Felkin–Anh model puts the largest group (or the most electron-withdrawing, σ*-accepting group) perpendicular to the C=O, anti to the incoming nucleophile, which then approaches along the Bürgi–Dunitz trajectory (about 107°) past the smallest substituent. When the α-substituent can chelate (OR, NR₂) and the metal can bridge (Mg²⁺, Zn²⁺, Ti⁴⁺), the chelation-controlled (Cram chelate) model locks the carbonyl and α-heteroatom syn and gives the opposite, anti-Felkin product. Prelog’s rule predicts the configuration of the α-hydroxy acid from Grignard addition to an α-keto ester of a chiral alcohol, the ester group acting as an internal chiral auxiliary.
Routes to single enantiomers. Resolution separates a racemate: classically through diastereomeric salts with a chiral acid or base, or enzymatically — a lipase acylates or hydrolyses one enantiomer much faster (kinetic resolution), so at most 50% of the material can be recovered as each enantiomer. Desymmetrisation converts a meso or prochiral compound into one enantiomer, with a theoretical yield of 100%: pig liver esterase hydrolyses one of the two enantiotopic esters of a meso diester. A chiral auxiliary is attached, directs a diastereoselective reaction and is removed: in the Evans aldol, the Z-boron enolate of an N-acyl oxazolidinone (from an amino alcohol) adds through a Zimmerman–Traxler chair in which the auxiliary’s substituent blocks one face and dipole minimisation orients the ring, giving the "Evans syn" aldol with very high diastereoselectivity; the auxiliary is then cleaved and recycled. Organocatalysis uses small chiral organic molecules: L-proline forms an enamine with acetone that adds to an aldehyde, the carboxylic acid hydrogen-bonding and directing the aldehyde in the transition state, to give the β-hydroxy ketone enantioselectively (with cyclohexanone as donor, the anti diastereomer) — the same enamine catalysis as in the intramolecular Hajos–Parrish–Eder–Sauer–Wiechert reaction.
Key takeaways
- Organometallic reactivity follows C–M ionicity (Li > Mg > Zn > Cu > B, Sn, Si); cuprates add 1,4; Wittig non-stabilised ylides give Z, stabilised E; β-silicon stabilises cations.
- Cross-couplings: oxidative addition, transmetallation, reductive elimination (B Suzuki, Sn Stille, Cu-acetylide Sonogashira, Zn Negishi, Mg Kumada, Si + F⁻ Hiyama); Heck uses β-H elimination instead; Tsuji–Trost via π-allyl; Buchwald–Hartwig makes C–N.
- Baylis–Hillman (DABCO), Henry (β-nitro alcohols), Ritter (amides from cations and nitriles), Sakurai (allylsilanes), Tebbe (methylenates esters), Pauson–Khand (cyclopentenones, three C–C bonds), Nazarov (4π conrotatory).
- Disconnect to synthons and match synthetic equivalents; dithianes are acyl-anion equivalents (umpolung); atom economy = product mass/reactant mass; orthogonal protection (TBS/F⁻, Bn/H₂, Boc/acid, Fmoc/base).
- LDA at −78 °C gives kinetic enolates; Z-enolates give syn aldols (boron enolates most cleanly); Felkin–Anh: L perpendicular, attack past S; chelation reverses it; resolution ≤ 50%, desymmetrisation up to 100%; Evans syn aldol; proline enamine catalysis.
Practice questions (18)
Attempt each one before opening the answer. Every explanation names the tempting wrong option as well as the right one, because that is where marks are lost.
Calculate the atom economy, in per cent to one decimal place, of the Wittig reaction Ph₃P=CH₂ (276.32 g/mol) + cyclohexanone (98.15 g/mol) → methylenecyclohexane (96.17 g/mol) + Ph₃PO.
Numerical answer — type the value.
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Answer: 25.7
Atom economy = 96.17/(276.32 + 98.15) × 100 = 96.17/374.47 × 100 = 25.7%. Three-quarters of the mass leaves as triphenylphosphine oxide, which is why the Wittig reaction scores poorly on this green-chemistry metric even at 100% yield.In an ideal enzymatic kinetic resolution of a racemic alcohol, what is the maximum percentage of the starting material that can be recovered as the unreacted, enantiopure alcohol?
Numerical answer — type the value.
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Answer: 50
A racemate is 50% of each enantiomer; the enzyme converts one and leaves the other, so at most 50% can be recovered as the unreacted enantiomer. Desymmetrisation of a meso compound, or a dynamic kinetic resolution that racemises the substrate, can exceed 50%.How many equivalents of methylmagnesium bromide are consumed when methyl benzoate is converted into 2-phenylpropan-2-ol?
Numerical answer — type the value.
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Answer: 2
The first equivalent adds to the ester and expels methoxide, giving acetophenone, which is more reactive than the ester and immediately takes a second equivalent; aqueous work-up gives the tertiary alcohol PhC(CH₃)₂OH. Stopping at the ketone needs a Weinreb amide or a cuprate.How many new carbon–carbon bonds are formed in an intermolecular Pauson–Khand reaction of an alkyne, an alkene and CO to give a cyclopentenone?
Numerical answer — type the value.
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Answer: 3
The five-membered ring joins one alkyne carbon to one alkene carbon, and the CO carbon to the other alkyne carbon and the other alkene carbon: three new C–C bonds in a formal [2 + 2 + 1] cycloaddition. Counting only the two bonds to CO misses the alkyne–alkene bond.Which step of the usual Pd-catalysed cross-coupling cycle is absent in the Heck reaction?
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Answer: A — Transmetallation
In the Heck reaction the aryl-Pd(II) species reacts with an alkene by migratory insertion and then β-hydride elimination, and base removes HX from Pd(II) to regenerate Pd(0); no organometallic partner is transmetallated. Insertion and β-H elimination are exactly the steps that replace it.Match the coupling to its nucleophilic partner. Which pairings are correct?
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Answer: A — Suzuki — arylboronic acid with base; B — Sonogashira — terminal alkyne with CuI and an amine; C — Hiyama — organosilane activated by fluoride
Suzuki uses boron, Sonogashira a copper acetylide formed in situ, and Hiyama a silane made nucleophilic as a fluorosilicate. Negishi uses organozinc reagents; organostannanes belong to the Stille coupling.The Tsuji–Trost reaction of a cyclic allylic acetate with sodium dimethyl malonate and Pd(PPh₃)₄ proceeds with overall
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Answer: A — retention, because Pd displaces acetate with inversion and the soft nucleophile attacks the π-allyl anti to Pd
Pd(0) attacks the allylic carbon anti to the acetate (first inversion) to give the η³-allyl Pd(II); a soft stabilised carbanion then attacks the allyl face opposite palladium (second inversion). Two inversions make net retention. Hard nucleophiles that attack Pd first give inversion instead.Why is the Tebbe reagent preferred to a Wittig reagent for converting an ester C=O into C=CH₂?
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Answer: A — The titanium methylidene is oxophilic enough to methylenate esters, giving enol ethers, which phosphorus ylides generally do not
Cp₂Ti=CH₂ forms a strong Ti–O bond through an oxatitanacyclobutane and so methylenates even ester and lactone carbonyls, and it is non-basic, so α-stereocentres survive. Wittig ylides react with aldehydes and ketones but not generally with esters.tert-Butanol in concentrated H₂SO₄ with acetonitrile, followed by water, gives
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Answer: A — N-tert-butylacetamide (Ritter reaction)
Acid forms the tert-butyl cation, the nitrile nitrogen captures it to give a nitrilium ion, and water adds to carbon; tautomerisation gives CH₃CONH–C(CH₃)₃. The C–N bond forms at nitrogen, not carbon, so no nitrile or ester results.In the Nazarov cyclisation, the key ring-forming step is
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Answer: A — a thermal 4π conrotatory electrocyclisation of a pentadienyl cation
Acid activation of the divinyl ketone gives a 3-oxypentadienyl cation with four π electrons over five carbons; the thermal Woodward–Hoffmann rule for 4π systems is conrotatory, which fixes the relative stereochemistry of the new ring. Elimination from the oxyallyl cation then gives the cyclopentenone.Deprotonation of 2-phenyl-1,3-dithiane with BuLi, alkylation with CH₃I and hydrolysis with HgCl₂ in aqueous acetonitrile gives
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Answer: A — acetophenone — the dithiane acts as a benzoyl anion equivalent
C2 of the dithiane, flanked by two sulfurs, is acidic; the carbanion is alkylated and Hg²⁺ unmasks the carbonyl, so the former aldehyde carbon becomes a ketone carbon bearing the new methyl: PhCOCH₃. This reversal of carbonyl polarity is umpolung (Corey–Seebach).Which deprotection conditions are correctly matched?
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Answer: A — TBS ether — tetrabutylammonium fluoride; B — Boc-amine — trifluoroacetic acid; C — Fmoc-amine — piperidine
The strong Si–F bond cleaves silyl ethers; Boc falls apart in acid to CO₂ and the tert-butyl cation; Fmoc is removed by base through E1cB elimination. Benzyl ethers are stable to base and are removed by hydrogenolysis (H₂, Pd/C) — which is what makes these four groups mutually orthogonal.2-Methylcyclohexanone is treated with LDA in THF at −78 °C and then with CH₃I. The main product is
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Answer: A — 2,6-dimethylcyclohexanone
The hindered base removes the more accessible C6 proton quickly and irreversibly at low temperature, forming the less substituted kinetic enolate, which is methylated at C6. Equilibrating conditions would give the more substituted enolate and 2,2-dimethylcyclohexanone; O-alkylation is minor with CH₃I.In a Zimmerman–Traxler aldol, a Z-boron enolate adds to an aldehyde RCHO. The product is predominantly
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Answer: A — the syn aldol
In the chair transition state the aldehyde R group takes the pseudo-equatorial position; with a Z-enolate the enolate substituent then ends up on the same side as the new OH, giving syn. E-enolates give anti. The short B–O bonds make boron enolates especially selective.A ketone is converted into its pyrrolidine enamine, which is then treated with methyl vinyl ketone and finally hydrolysed. The enamine served as
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Answer: A — a neutral enolate equivalent that adds to the Michael acceptor at carbon
The nitrogen lone pair makes the enamine β-carbon nucleophilic, so it adds 1,4 to methyl vinyl ketone; hydrolysis of the iminium releases the 1,5-diketone (Stork enamine Michael reaction). Enamines avoid strong bases and polyalkylation.In the Felkin–Anh model for nucleophilic addition to an α-chiral ketone with small (S), medium (M) and large (L) α-substituents, the nucleophile approaches
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Answer: A — anti to L, which is perpendicular to the C=O, along the Bürgi–Dunitz angle past S
The reactive conformer has L perpendicular to the carbonyl; the nucleophile attacks at about 107° to C=O on the face opposite L, and of the two such conformers the one where it passes the small group is preferred. An α-alkoxy group with a chelating metal overrides this and gives the chelation (anti-Felkin) product.In the L-proline-catalysed intermolecular aldol reaction of acetone with an aldehyde, the catalyst activates acetone by forming
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Answer: A — a chiral enamine, while its carboxylic acid hydrogen-bonds and orients the aldehyde
Proline’s secondary amine condenses with acetone to an enamine (a raised-HOMO nucleophile), and the carboxylic acid delivers the aldehyde to one face through a hydrogen-bonded, Zimmerman–Traxler-like transition state, giving the aldol enantioselectively; hydrolysis releases the catalyst. No metal enolate is involved.Pig liver esterase hydrolyses only one of the two ester groups of a meso diester, giving a single enantiomer of the monoacid. This strategy is called
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Answer: A — desymmetrisation, with a theoretical yield of 100%
The two esters of a meso diester are enantiotopic; distinguishing them converts the whole achiral substrate into one enantiomer, so the yield is not capped at 50% as in resolving a racemate. No auxiliary is attached or removed.