Chapter 37 — Quiz

Twenty-five questions on transition-metal organometallic chemistry. ∗ marks questions answered in the answer key.

Multiple choice

1.∗ A Pd cross-coupling catalytic cycle starts with: (a) Pd(0) (b) Pd(II) (c) Pd(IV) (d) Pd(I)

2.∗ Oxidative addition increases the metal's oxidation state by: (a) +2 (b) -2 (c) 0 (d) +4

3.∗ Reductive elimination: (a) forms a new C-C bond and reduces the metal by 2 oxidation states (b) breaks bonds and oxidizes the metal (c) only happens at Pd(IV) (d) is the same as oxidative addition

4.∗ Suzuki coupling uses: (a) aryl boronic acid (ArB(OH)₂) (b) aryl silane (c) aryl chloride only (d) aryl iodide only

5.∗ The Heck reaction couples: (a) aryl halide + alkene → aryl-substituted alkene (b) aryl halide + amine (c) only two aryl halides (d) aryl halide + ester

6.∗ Buchwald-Hartwig amination forms: (a) a C-N bond between an aryl halide and an amine (b) a C-C bond (c) a C-O bond (d) a C-S bond

7.∗ The Grubbs catalyst is a: (a) Ru carbene complex (b) Pd-phosphine complex (c) Mo alkylidene (d) Cu acetylide

8.∗ Ring-closing metathesis (RCM): (a) converts a diene into a cyclic alkene + ethylene (b) closes the ring with no byproducts (c) only works with allylic alcohols (d) is photochemical

9.∗ Ziegler-Natta polymerization makes: (a) low-density polyethylene (LDPE) (b) high-density polyethylene (HDPE; linear) (c) only polypropylene (d) only PVC

10.∗ The 2010 Nobel Prize in Chemistry was awarded to: (a) Heck, Negishi, Suzuki (for Pd cross-coupling) (b) Sharpless only (c) Schrock and Grubbs only (d) Knowles only

11.∗ Why does Pd(0) preferentially undergo oxidative addition with Ar-I over Ar-Br? (a) Ar-I has a weaker C-I bond, so it's easier to break (b) Ar-I is more polar (c) Ar-Br is too inert (d) the iodide has a smaller atomic radius

12.∗ Why does the Heck reaction give E-alkenes? (a) the migratory insertion + β-H elimination geometry favors the trans product (b) it's the kinetic product (c) E is always preferred regardless (d) cis-alkenes are not formed

13.∗ A Sonogashira coupling requires: (a) Pd + Cu co-catalyst + aryl halide + terminal alkyne + amine base (b) only Pd (c) only Cu (d) photocatalysis

14.∗ Why is the Buchwald-Hartwig amination preferred over direct nucleophilic substitution of aryl halides with amines? (a) direct substitution doesn't work for aryl halides without strong activating groups; Buchwald uses Pd to enable it (b) Buchwald is faster (c) Buchwald uses cheaper reagents (d) all of the above

15.∗ Olefin metathesis works by: (a) a metal carbene exchanging substituents on two alkenes via a metallacyclobutane (b) Pd cross-coupling (c) a free radical mechanism (d) photochemistry

16.∗ Ring-opening metathesis polymerization (ROMP): (a) opens strained cyclic alkenes (e.g., norbornene) and polymerizes them (b) closes rings (c) cross-couples two alkenes (d) only works with aromatic rings

17.∗ Why does ethylene release drive RCM forward? (a) thermodynamics: ethylene is a small, volatile gas; removing it shifts the equilibrium toward the cyclic product (b) kinetics (c) hydrogen bonding (d) electronic effects

18.∗ Modern metallocene polymerization (e.g., zirconocene) controls: (a) tacticity (isotactic, syndiotactic, atactic) of polypropylene and other polyolefins (b) molecular weight only (c) crystallinity only (d) all of the above

19.∗ A bulky phosphine ligand (e.g., SPhos, XPhos) on Pd: (a) accelerates Pd-catalyzed coupling of aryl chlorides (b) slows the reaction (c) only works for aryl iodides (d) decomposes the catalyst

20.∗ C-H activation in modern catalysis: (a) selectively functionalizes a specific C-H bond, often using directing groups (b) cleaves all C-H bonds (c) is photochemical only (d) only works on alkenes

Short answer

21. Sketch the four-step cycle of Suzuki coupling. Show: Pd(0) + Ar-X → OA → transmetalation → RE → product + Pd(0). Identify each step.

22. Predict the product of: 4-bromoacetophenone + phenylboronic acid + Pd(PPh₃)₄ + K₂CO₃ in dioxane. Explain why the ketone is preserved.

23. Compare the Suzuki, Heck, Sonogashira, and Buchwald-Hartwig couplings. What new bond is formed in each? What is the second coupling partner in each?

24. Sketch the mechanism of ring-closing metathesis on a 1,7-diene to form a 6-membered ring + ethylene.

25. Why is Pd-catalyzed cross-coupling so popular in pharmaceutical synthesis (~30% of drugs use it)? Identify three reasons.

Answer key

  1. a — Pd(0) starts the cycle.
  2. a — OA increases oxidation state by 2.
  3. a — RE forms C-C bond and reduces metal.
  4. a — Suzuki uses boronic acid.
  5. a — Heck couples aryl halide + alkene.
  6. a — Buchwald-Hartwig forms C-N bond.
  7. a — Grubbs is Ru carbene.
  8. a — RCM gives cyclic alkene + ethylene.
  9. b — Z-N gives linear HDPE.
  10. a — 2010 Nobel: Heck, Negishi, Suzuki.
  11. a — Ar-I has weaker bond.
  12. a — Geometry of MI + β-H elim favors trans.
  13. a — Sonogashira uses Pd + Cu + amine.
  14. a — Buchwald enables the otherwise-difficult direct substitution.
  15. a — Metathesis via metallacyclobutane.
  16. a — ROMP opens strained rings.
  17. a — Ethylene release shifts equilibrium.
  18. a — Metallocene controls tacticity.
  19. a — Bulky phosphine enables Ar-Cl coupling.
  20. a — C-H activation is selective with directing groups.

21. Suzuki coupling cycle: - Step 1 (OA): Pd(0) + Ar-X → Pd(II)(Ar)(X). Pd inserts into the C-X bond. - Step 2 (Transmetalation): Pd(II)(Ar)(X) + Ar'-B(OH)₂ + K₂CO₃ → Pd(II)(Ar)(Ar') + X-B(OH)₂... + KX. The base activates the boronic acid for transfer; the Ar' goes from B to Pd. - Step 3 (RE): Pd(II)(Ar)(Ar') → Pd(0) + Ar-Ar'. The two aryls combine to form the biaryl product; Pd(0) is regenerated. - Pd(0) re-enters the cycle. Catalytic.

22. 4-Bromoacetophenone has a Br on one ring and a C(=O)CH₃ group para. Phenylboronic acid has Ph-B(OH)₂. Suzuki conditions: Pd(PPh₃)₄ + K₂CO₃. The Pd cycle: OA at the C-Br bond → Pd(II)(4-acetophenyl)(Br); transmetalation with PhB(OH)₂ → Pd(II)(4-acetophenyl)(Ph); RE → 4-phenylacetophenone (4-PhC₆H₄-CO-CH₃) + Pd(0). The ketone is preserved because: (1) the C=O is not a substrate for OA (Pd doesn't insert into a C=O bond at neutral conditions). (2) The base is mild (K₂CO₃) and doesn't hydrolyze the ester or attack the carbonyl significantly. Net: the Br is replaced by Ph; everything else is unchanged.

23. Comparison: - Suzuki: Ar-X + Ar'-B(OH)₂ → Ar-Ar'. Forms new biaryl C-C bond. Coupling partner: aryl boronic acid. - Heck: Ar-X + alkene (CH₂=CHR) → Ar-CH=CHR. Forms new aryl-vinyl C-C bond. Coupling partner: alkene. - Sonogashira: Ar-X + HC≡C-R → Ar-C≡C-R. Forms new aryl-alkyne C-C bond. Coupling partner: terminal alkyne. Co-catalyst: Cu(I). - Buchwald-Hartwig: Ar-X + HNR'₂ → Ar-NR'₂. Forms new C-N bond. Coupling partner: amine.

All start with OA at the aryl halide; differ in transmetalation step and product.

24. RCM on 1,7-octadiene (CH₂=CH-(CH₂)₄-CH=CH₂): 1. Grubbs catalyst (Ru=CHR) reacts with one terminal CH₂=CHR' alkene. [2+2] cycloaddition gives a metallacyclobutane. 2. The metallacyclobutane opens in the productive direction: Ru=CHR' (a new carbene) + CH₂=CHR'' (released ethylene? actually "alkylidene exchange"). 3. The new Ru=CHR' is now attached to one end of the original substrate. It encounters the OTHER terminal alkene of the substrate. 4. [2+2] cycloaddition gives another metallacyclobutane. 5. Productive opening releases ethylene (CH₂=CH₂) and gives a new Ru=CHR'' that is attached to the cyclized product. 6. The cyclized product is a 6-membered ring with one C=C (the new metathesis-formed alkene). Plus ethylene is released, driving the equilibrium toward the ring. Final product: cyclohexene + ethylene + regenerated Grubbs catalyst.

25. Pd cross-coupling is popular because: - Functional group tolerance: tolerates -OH, -COOH, -CHO, -NH₂, etc. - Mild conditions: room temperature to mild reflux; aqueous or organic solvent. - Scalable: many Pd reactions go to ton scale industrially. - Predictable selectivity: regioselectivity is controlled by the halide; stereoselectivity (when a stereocenter is formed) often by chiral ligands. - Wide substrate scope: most aryl halides and most coupling partners (boronic acids, alkenes, amines) are commercially available. - Low catalyst loading: 0.1-5 mol% Pd typical; cost-effective. - Shared mechanism: once you understand the OA/transmetalation/RE cycle, you understand all the variants (Suzuki, Negishi, Heck, etc.). These features together make Pd cross-coupling the preferred method for many C-C and C-N bond formations in modern medicinal chemistry.