Chapter 37 — Exercises

Fifty problems on transition-metal organometallic chemistry. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Catalytic cycle elementary steps

37.1∗ (routine) Draw the four elementary steps of Pd cross-coupling: oxidative addition, transmetalation, reductive elimination, and the cycle starting Pd(0).

37.2 (routine) What is the oxidation state change in: (a) oxidative addition, (b) reductive elimination?

37.3∗ (routine) Why does Pd(0) preferentially undergo oxidative addition with Ar-I > Ar-Br > Ar-Cl > Ar-F? Connect to bond strength.

37.4 (moderate) A reaction stops at the Pd(II) intermediate (no reductive elimination). What might be the cause? Suggest two structural reasons.

37.5 (moderate) β-Hydride elimination is the reverse of migratory insertion. Why is it sometimes a problem in catalysis? When is it desirable (in Heck reactions)?

37.6 (challenge) Draw the migratory insertion step where a Pd-H bond inserts into a C=C of styrene. Show the geometry: which face of the C=C does the H add to?

Section B — Suzuki coupling

37.7∗ (routine) Predict the product: (a) PhBr + PhB(OH)₂ + Pd(PPh₃)₄ + K₂CO₃ → ? (b) 4-bromobenzoic acid + 4-methoxyphenylboronic acid + Pd + K₂CO₃ → ? (c) PhBr + PhBpin (pinacol boronate) + Pd → ? (similar to Suzuki)

37.8 (routine) Sketch the mechanism of Suzuki coupling, showing OA, transmetalation, RE.

37.9 (moderate) What is the role of the base (K₂CO₃) in Suzuki coupling? Hint: it activates the boronic acid for transmetalation.

37.10 (moderate) Why do bulky phosphine ligands (e.g., SPhos, XPhos) enable Suzuki coupling of aryl chlorides? Connect to the slow oxidative addition of Ar-Cl.

37.11 (challenge) Design a Suzuki coupling to make: 4-methylbiphenyl from 4-methylbromobenzene. What boronic acid do you need? What conditions?

37.12 (challenge) A Suzuki coupling fails because the substrate has a free -COOH group. Why? What can you do to enable it (protect the COOH as ester)?

Section C — Heck reaction

37.13∗ (routine) Predict the product: (a) PhBr + CH₂=CHCO₂Et + Pd(OAc)₂ + Et₃N → ? (b) 4-iodoanisole + CH₂=CHCO₂Me + Pd → ? (c) PhBr + 1-decene + Pd → ? (note: terminal alkene)

37.14 (routine) Why does the Heck reaction give a (E)-alkene preferentially? Connect to migratory insertion + β-H elimination geometry.

37.15 (moderate) Sketch the mechanism of Heck: OA → MI (alkene inserts into Pd-Ar) → β-H elimination → base regenerates Pd(0).

37.16 (challenge) Design a Heck reaction to make: trans-cinnamaldehyde from bromobenzene + acrolein.

Section D — Sonogashira and Negishi

37.17∗ (routine) Predict the product: (a) PhBr + HC≡C-TMS + Pd(PPh₃)₂Cl₂ + CuI + Et₃N → ? (b) 4-bromoiodobenzene + HC≡C-Ph + Pd + CuI → ? (note: chemoselectivity: which halide reacts?) (c) Iodobenzene + ZnEt₂ + Pd → ? (Negishi-style)

37.18 (routine) Why does Sonogashira require Cu co-catalyst? What is its role?

37.19 (moderate) Compare Negishi (organozinc), Suzuki (organoboronic acid), and Stille (organotin) cross-couplings. Which is most functional-group tolerant?

37.20 (challenge) Why is the Negishi coupling preferred over Suzuki for sp³-sp² couplings (alkyl-aryl)?

Section E — Buchwald-Hartwig amination

37.21∗ (routine) Predict the product: (a) PhBr + Et₂NH + Pd + ligand + Cs₂CO₃ → ? (b) 4-bromopyridine + piperidine + Pd → ? (c) 4-bromobenzonitrile + morpholine + Pd → ?

37.22 (moderate) Why does direct nucleophilic attack of an amine on an aryl halide (without Pd) usually fail? Connect to the slow SNAr mechanism.

37.23 (challenge) Buchwald-Hartwig is now used for large-scale drug synthesis (e.g., for sitagliptin). Why is this preferred over alternative methods?

Section F — Olefin metathesis

37.24∗ (routine) Predict the product of: (a) Ring-closing metathesis (RCM) of CH₂=CH-(CH₂)₅-CH=CH₂ + Grubbs cat → ? (b) Cross-metathesis of CH₂=CHEt + CH₂=CHPh + Grubbs cat → ? (c) Ring-opening metathesis polymerization (ROMP) of norbornene + Grubbs cat → ?

37.25 (routine) What is the catalyst in: (a) Grubbs metathesis, (b) Schrock metathesis? Compare reactivity and functional group tolerance.

37.26 (moderate) Sketch the mechanism of ring-closing metathesis: M=CHR + alkene → metallacyclobutane → new M=CHR' + new alkene.

37.27 (moderate) Why does ethylene release drive RCM forward? Connect to thermodynamics.

37.28 (challenge) Design a synthesis of a 12-member macrocyclic alkene from a linear diene using RCM.

37.29 (challenge) Why does Grubbs II work in air with most functional groups, while Schrock catalyst requires inert atmosphere?

Section G — Polymerization

37.30∗ (routine) Compare Ziegler-Natta polymerization (TiCl₄ + AlEt₃) of: (a) ethylene → ? (b) propylene → ? (specify tacticity)

37.31 (routine) Why does HDPE (high-density polyethylene, Ziegler-Natta) have linear chains while LDPE (low-density polyethylene, radical) has branched chains?

37.32 (moderate) What is metallocene catalysis? Why does it give better tacticity control than Ziegler-Natta?

37.33 (challenge) Sketch the mechanism of alkene polymerization via Ziegler-Natta. Identify the key migratory insertion step.

Section H — C-H activation

37.34∗ (routine) What is C-H activation? Why is it the "holy grail" of organic chemistry?

37.35 (moderate) A directing group on an aromatic ring enables Pd-catalyzed C-H activation at a specific position. Sketch a generic example: aryl ring + ortho-directing group + Pd + electrophile → ortho-functionalized product.

37.36 (challenge) Compare ortho-directed C-H activation with traditional Friedel-Crafts: which is more controllable? Which has more limitations?

Section I — Asymmetric catalysis

37.37∗ (routine) What is BINAP? What kind of chiral catalysis does it enable?

37.38 (routine) Sketch the Noyori asymmetric hydrogenation: ketone + H₂ + Ru/BINAP → chiral alcohol. Identify the role of BINAP.

37.39 (moderate) What is the L-DOPA synthesis (Knowles, asymmetric hydrogenation)? Identify the chiral catalyst (DiPAMP) and the substrate (an α,β-unsaturated acid).

37.40 (challenge) Modern asymmetric catalysis: design an asymmetric Heck reaction. What chiral ligand would you use?

Section J — Industrial applications

37.41 (routine) Pd cross-coupling is used in 20-40% of drug syntheses. Why is it so popular? Identify three reasons.

37.42 (routine) Why is the original Stille coupling (organotin) less commonly used today than Suzuki (organoboronic acid)? Connect to environmental concerns.

37.43 (moderate) Hydroformylation: alkene + H₂ + CO + Co or Rh catalyst → aldehyde. Sketch the mechanism. Why is this industrially important?

37.44 (challenge) The Wacker process (Pd/Cu + ethylene + O₂ → acetaldehyde) was the first homogeneous catalytic process at industrial scale. Why was it revolutionary?

Section K — Multistep synthesis

37.45∗ (routine) Design a synthesis of an aromatic biaryl using Suzuki coupling.

37.46 (moderate) Design a synthesis of a complex amine drug using Buchwald-Hartwig amination + reductive amination.

37.47 (moderate) Design a synthesis of a 14-member macrocyclic lactone using RCM.

37.48 (challenge) Combine multiple Pd cross-couplings: design a 3-step synthesis using sequential Suzuki + Heck + Sonogashira on a polyhalogenated substrate.

37.49 (challenge) Design a stereoselective synthesis using asymmetric hydrogenation (Noyori) for the chiral center, then Suzuki coupling for the biaryl framework.

37.50 (challenge) Open-ended: choose a real complex pharmaceutical and trace its synthesis. Identify any Pd cross-couplings, metathesis, or asymmetric organometallic steps. Compare to the alternative non-organometallic routes.

Notes for instructors: Common stumbling blocks for Chapter 37: (1) Confusing OA, MI, RE — the elementary steps. (2) Mismatching Pd cross-couplings (Suzuki vs Heck vs Stille). (3) Forgetting that ethylene release drives RCM. (4) Thinking C-H activation is easy. Computational exercises: visualize Pd's d-orbital interactions during OA and RE; predict catalyst design for new substrates.