Preparatory Problems2 PDF

52nd International Chemistry Olympiad, Istanbul, TURKEY Preparatory problems: THEORETICAL
Problem 14. Platinum Complexes as Anticancer Drugs
Medicinal inorganic chemistry based on metal‐based drugs is broadly defined as the area of
research related to metal ions and metal complexes and their clinical applications. It is a new
research area that developed from the discovery of the anticancer agent cisplatin. Cisplatin, cis-
diamminedichloroplatinum(II), is a yellow powder and an anticancer drug widely used in the
treatment of a variety of tumors, especially those of the testes, ovaries, head, and neck.
The synthesis of cisplatin starts with K2[PtCl4], but has undergone several improvements since
it was published more than 100 years ago. The main problem is the occurrence of impurities
and the formation of the by-product trans-platin. Nowadays, the synthetic routes are mostly
based on a method published in the 1970s by Dhara. In the initial step, K2[PtCl4] is reacted with
excess KI, and the platinum complex is converted into the iodo analogue (A). Subsequently,
NH3 is added to the compound A and compound B is formed by ligand exchange in which two
NH3 ligands are exchanged with two iodo ligands. B is a yellow solid that is filtered, dried, and
mixed with the aqueous solution of AgNO3. The insoluble AgI can be filtered off and cis-
diamminediaquaplatinum(II) nitrate (C) is formed; then excess KCl is added to the solution of
C to yield cisplatin (D).
The success of the synthesis relies on the strong trans effect of the iodo ligands. The spectator
ligands T that are trans to the leaving group in square-planar complexes influence the rate of
substitution. This phenomenon is called the trans effect. Key point is that a strong σ-donor
ligand or π-acceptor ligand greatly accelerates substitution of a ligand situating in the trans
position. Trans effects follow the order given below.
- - - - - - - -
For a T σ -donor: OH < NH3 < Cl < Br < CN , CH3 < I < SCN < PR3, H
- - - - -
For a T π-acceptor: Br < I < NCS < NO2 < CN < CO, C2H4
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14.1. Write the formulas of A–D.
14.2. Draw molecular structures of A–D.
14.3. Is the complex D polar?
14.4. Sketch the d-orbital splitting of cisplatin complex D in view of Crystal Field Theory and
show the electron distribution diagram.
14.5. Determine magnetic nature of complex A.
The platinum complex binds to DNA and causes cross-linking, which triggers the programmed
cell death (apoptosis). However, the other geometrical isomer of the square planar structure
transplatin, trans-diamminedichloroplatinum(II) (F), is not effective for the treatment of cancer.
Transplatin is synthesized starting from [Pt(NH3)4]2+ to which the first and second Cl– ligands
are added to form transplatin (F) as represented in the scheme below.
14.6. Draw the molecular structures of E and F.
The most important classes of antitumor agents, cisplatin, carboplatin, and oxaliplatin as
platinum(II) diamines are widely used in chemotherapy to treat a wide variety of cancers.
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However, the therapeutic index of these agents is relatively narrow; their use is often plagued
with severe toxicity and the development of resistance, which leads to disease progression.
Recently, oxoplatin, iproplatin, ormaplatin and satraplatin are Pt complexes that have been used
clinically (oxoplatin) or in clinical trials.
14.7. All complexes have the same geometry and oxidation number for the Pt central atom.
Write the oxidation state of Pt and geometry of the complexes.
14.8. Which Pt complex, cisplatin or satraplatin, is kinetically more inert for substitution
reactions?
14.9 Oxaplatin is an isomer of [Pt(NH3)2Cl2(OH)2] complex. Draw all stereoisomers and

indicate the chiral one(s).
Platinum complexes (oxoplatin, iproplatin, ormaplatin, and satraplatin) can be considered

prodrugs that are primarily intracellularly activated by biological reducing agents such as thiols,
ascorbic acid, and glutathione (GSH) to kill cancer cells.
In a study, for example, the reduction of cis,trans,cis-[PtCl2(OCOCH3)2(NH3)2] (G, prodrug),

which has a similar structure to satraplatin, by aqueous extract of cancer cells (A2780,
A2780cisR, and HT-29) yields cisplatin (D, drug) and free acetate ion as given below.
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14.10. Draw the molecular structure of G.
14.11. Sketch the d-orbital splitting of the metal ion in G and write the electronic configuration.
14.12. Decide whether G is paramagnetic or diamagnetic.
14.13. The complex G crystallizes into a monoclinic crystal system of parameters: the lengths
of the unit cell: a = 14.9973, b = 8.57220, c = 11.1352 Å, the β angle in the unit cell = 126.7690°,
the number of the molecules in the unit cell (Z) = 4, M = 436.16 g/mol (the complex has one
water molecule in the crystal structure).
Calculate the density (ρ) of the complex.
Hint: the volume of a monoclinic crystal unit cell is 𝑉 = 𝑎 × 𝑏 × 𝑐 × sin 𝛽
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52nd International Chemistry Olympiad, Istanbul, TURKEY Preparatory problems: THEORETICAL

Problem 14. Platinum Complexes as Anticancer Drugs

14.1. Write the formulas of A–D.

14.2. Draw molecular structures of A–D.

14.3. Is the complex D polar?

14.5. Determine magnetic nature of complex A.

14.6. Draw the molecular structures of E and F.

Write the oxidation state of Pt and geometry of the complexes.

14.9 Oxaplatin is an isomer of [Pt(NH3)2Cl2(OH)2] complex. Draw all stereoisomers and

Platinum complexes (oxoplatin, iproplatin, ormaplatin, and satraplatin) can be considered

In a study, for example, the reduction of cis,trans,cis-[PtCl2(OCOCH3)2(NH3)2] (G, prodrug),

14.10. Draw the molecular structure of G.

14.12. Decide whether G is paramagnetic or diamagnetic.

Calculate the density (ρ) of the complex.

Hint: the volume of a monoclinic crystal unit cell is 𝑉 = 𝑎 × 𝑏 × 𝑐 × sin 𝛽

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