Advanced Organic Chemistry Practice Problems 2021 Direct

While the MCAT does not test "advanced" organic chemistry to the depth of a graduate course, 2021 prep books from Kaplan and Princeton Review updated their practice banks to remove archaic reactions (like certain heavy-metal oxidations) in favor of greener chemistry and biological applications (enzyme mechanisms).

Scenario:
A graduate student attempts a Suzuki-Miyaura coupling between 2-bromopyridine (aryl halide) and 2-thienylboronic acid (heteroaromatic boronic acid) using $\textPd(PPh_3)_4$ in toluene/water with $\textNa_2\textCO_3$ at $80^\circ\textC$. The reaction yields <5% product.

Question: Identify the two sources of failure.

The 2021 Solution:

Remediation (Advanced):

1. Cycle: Pd(II) ligation → C–H cleavage via concerted metalation-deprotonation (CMD) → oxidation with NFSI to Pd(IV) → reductive elimination to C–F bond. Ligand L1 creates a chiral pocket, blocking approach to less hindered C–Hs.

2. Product: Cyclopentyl-4-trifluoromethylbenzene. Mechanism: Ni(0) oxidative addition into Ar–Br → transmetalation with alkyl-BF₃K (base-assisted) → Ir(III)* excited state reduces Ni(II) to Ni(0) via SET, closing cycle.

3. The phosphate binds the isoquinolinium ion via H-bonding and π-stacking, shielding one enantioface. At higher T, the ion pair dissociates partially, reducing stereoinduction.

4. Endo monomer + fast initiation → isotactic polymer due to facial bias from chiral substituent. Z-selective catalyst gives cis double bonds in backbone, reducing conjugation and altering mechanical properties. advanced organic chemistry practice problems 2021

5. Au: 5-endo-dig cyclization to furan. Pt: alkyne activation, cyclopropanation, electrocyclic ring opening to phenol via carbonyl ylide.

6. Ir(III) undergoes oxidative addition into H₂ (or T₂) → C–H activation via σ-bond metathesis at electron-rich C(sp³) → reductive elimination of H-T into the same position. Aromatic C–Hs are too acidic and not accessible under neutral, non-polar conditions.

Conditions: [³H]₂ gas (1 Ci), Crabtree’s catalyst ([Ir(cod)(PCy₃)(py)]PF₆, 2 mol%), DCM, –20 °C, 30 min.

Substrate: An estradiol derivative with an unactivated tertiary C–H at C-9. While the MCAT does not test "advanced" organic

Observation: 85% incorporation of tritium at C-9 only.

Questions:
a) Draw the catalytic cycle for H/D or H/T exchange via Ir(III)-dihydride intermediates.
b) Why does the reaction not label aromatic C–H bonds under these mild conditions?
c) Propose a deuterium control experiment to confirm the mechanism.

Reaction: An enantioenriched chiral phosphoric acid (CPA, 5 mol%) catalyzes the addition of a silyl ketene acetal to an N-Boc isoquinolinium ion generated in situ from 3,4-dihydroisoquinoline and Boc₂O.

Observation: The product, a tetrahydroisoquinoline derivative, is formed in 94% ee. Remediation (Advanced):

Questions:
a) Draw the transition state model explaining the facial selectivity.
b) How does the counteranion (chiral phosphate) influence the electrophile’s trajectory?
c) If the reaction is run at 0 °C instead of –78 °C, the ee drops to 72%. Why?