Synthesis

As you may well have noticed, you have chosen to view the synthesis page - the page that is separated from the rest. No this is not a mistake, but the result of a long, hard thought-out decision. This page contains most of the hard-core chemistry of cisplatin, which unfortunately is very difficult to incorporate into the main text without disrupting the general flow of biomedical topics.

Most inorganic texts do not describe the synthesis of cisplatin in any great detail, just basic outlines. ^{¤ , ¤} A few examples include:

• Addition of ammonia to ammonium tetrachloroplatinum(II)
• Heating of tetraammineplatinum(II) chloride at 250°C
• Reaction of ammonium carbonate with tetrachloroplatinic(II) acid

This clearly would not warrant an entire page to be devoted to cisplatin synthesis, so... after some intense research, I have managed to locate and obtain the necessary text dating back to 1946, ^{¤ , ¤} to come up with an actual step-by-step procedure for the synthesis of cisplatin.

Synthesis of Cisplatin

Overall reaction scheme:

Preparation of potassium tetrachloroplatinate(II):

1. To a suspension of 9.72g (0.02mol) of potassium hexachloroplatinate(IV) in 100cm³ of water, in a 250cm³ beaker, is added in small portions 1.0g (0.01mol) of hydrazine dihydrochloride.
   

   Excess hydrazine dihydrochloride must be avoided to prevent the formation of hydrazine complexes and reduction of potassium hexachloroplatinate(IV) to platinum when the solution is made basic with ammonia during cisplatin synthesis.

   
   
2. The mixture is stirred mechanically while the temperature is raised to 50-65°C over a period of 5-10 minutes. This temperature is mantained for about 2 hours, until only a small amount of yellow potassium hexachloroplatinate(IV) remains in the deep red solution.
   

   An insoluble hexachloroplatinate(IV) is used to indicate when the reaction is complete.

   
   
3. The temperature is then raised to 80-90°C to ensure completion of the reaction, and the mixture is cooled in an ice bath and filtered to remove unreacted potassium hexachloroplatinate(IV).
   

   Use of excess potassium hexachloroplatinate(IV) prevents the reduction to metallic platinum.

   
   
4. The latter is washed with several 10cm³ portions of ice-water until the washings are colourless. The washings, combined with the deep red filtrate, contain pure potassium tetrachloroplatinate(II) and HCl(aq). Half of this solution is used to make the cisplatin.

   This portion is equivalent to/can be replaced with: 4.15g (0.01moldm^-3 of potassium tetrachloroplatinate(II) + 2.5cm³ of concentrated HCl + 75cm³ of water.

Preparation of cis-[Pt(NH₃)₂Cl₂]:

1. 3g of ammonium chloride is dissolved in 1 portion of the potassium tetrachloroplatinate(II), in a 150cm³ beaker.

   Use of an unbuffered solution may result in formation of hydroxo complex.

   
   
2. Approximately 10cm³ of 3moldm^-3 aqueous ammonia is cautiously added until the solution is neutral to litmus. 0.02mol of additional aqueous ammonia (6.75cm³ of 3moldm^-3), is then added.

   A slight excess of aqueous ammonia is not harmful, however, a large excess will markedly decrease the yield by formation of tetraammineplatinum(II) chloride.

   
   
3. The solution is refrigerated for 24-48 hours until the precipitation of the greenish yellow solid apears to be complete and the supernatant liquid has changed from deep red to light yellow.
   
   
   
4. The precipitate, consisting of the cis isomer containing a small amount of tetraammineplatinum(II)tetrachloroplatinate(II) (Magnus' green salt, [Pt(NH₃)₄][PtCl₄]), is separated by suction filtration and washed free of soluble salts with several 10cm³ portions of ice water.
   
   
   
5. The precipitate is then transferred to a 250cm³ Erlenmeyer flask, and 0.1 N of aqueous hydrochloric acid is added to bring the total volume to 150cm³.
   

   Dilute acid rather than water is used for the recrystallisation to prevent formation of aquo complexes.

   
   
6. This mixture is heated to boiling and stirred until all the cis isomer dissolves, leaving a small residue of Magnus' green salt, which is removed by filtration.

   Crystallisation of the cis isomer is prevented by the use of a funnel heater or a jacketed Büchner funnel.

   
   
7. The residue on the filter paper is washed with 10-20cm³ of boiling 0.1 N of aqueous hydrochloric acid and the washings are added to the filtrate.
   
   
   
8. The latter is cooled in an ice bath for 1-2 hours until crystallisation seems complete.
   
   
   
9. The yellow crystals are separated by suction filtration, washed with several 10cm³ portions of ice water, and air-dried.
   
   
   
10. The yield is 1.80g (60% based on potassium hexachloroplatinate(IV)).

    The limiting reagent is actually hydrazine dihydrochloride; so the yield is really slightly higher.

The substitution of the first chloride ligand is obviously non-specific, the second however, occurs cis to the first substituted which has now become an ammonia group. This is due to the greater trans-effect of the chloride relative to the ammonis, which is defined as "the effect of a coordinated group on the rate of substitution reactions of ligands opposite to it in a metal complex". The magnitude of this effect is determined by the sigma-donor or pi-acceptor ability of ligands trans to the out-going ligand.

For the sigma-trans-effect, a polarisable strong trans-sigma-donor ligand T, will have its electron density distributed more towards the out-going ligand X. Therefore, at the trigonal bipyramidal transition state, T will have greater overlap with the empty P-sigma orbital, thus lowering the energy to reach the transition state. The sigma-trans-directing series of a select few ligands are as shown:

H^- > PR₃ > -SCN^- > I^- > CH₃^- > CO > CN^- > Br^- > Cl^- > NH₃ > OH^-

This list shows chloride to have a greater sigma-trans-efect than ammonia.

For the pi-trans-effect, a trans-pi-acceptor ligand T, can form pi bonds with the metal and withdraw electron density away from the out-going ligand X. Consequently, the decreased electron density around X will attract incoming nucleophilic ligands Y, and also stabilise the trigonal bipyramidal transition state. The pi-trans-directing series of a select few ligands are as follows:

CH₂=CH₂ > CO > CN^- > -NO₂ > -SCN^- > I^- > Br^- > Cl^- > NH₃ > OH^-

Again, this list shows chloride to also have a greater pi-trans-effect than ammonia. Overall, both sigma- and pi- effects work towards lowering the energy to the transition state.

The effects of sigma- and pi- trans-effects on the transition state energy
(Dr. B. Young, 1998)

For completeness, the basic procedure for the preparation of transplatin is to add excess ammonia to the second portion of potassium tetrachloroplatinate(II) and stir for a few hours to give tetraammineplatinum(II) chloride. This is then heated in the presence of excess chloride to give transplatin. Again, this follows the trans-effect series. The first chloride substituted into the complex directs the second in-coming chloride to a position trans to it as it is a stronger trans-director.

Several tests are available for distinguishing between the two isomers of diamminedichloroplatinum(II). One of which is the classical Kurnakov test: In hot aqueous solution, the cis compound reacts with aqueous thiourea to give a deeper yellow solution from which yellow needles of tetrakis (thiourea) platinum(II)chloride deposit on cooling, while the trans compound gives a colourless solution from which snow white needles of trans-bis(thiourea)diaammineplatinum(II) deposit on cooling.