NYJC H3 Chemistry P1 Answers

[Turn over NANYANG JUNIOR COLLEGE JC2 PRELIMINARY EXAMINATION Higher 3 PHARMACEUTICAL CHEMISTRY 9812/01 Paper 1 29 September 2014 2 hours 30 minutes Additional Materials: Answer Paper Data Booklet READ THESE INSTRUCTIONS FIRST Write your name and class on all the work you hand in. Write in dark blue or black pen on both sides of the paper. You may use a soft pencil for any diagrams, graphs or rough working. Do not use staples, paper clips, highlighters, glue or correction fluid. Answer any five questions. At the end of the examination, fasten all your work securely together. The number of marks is given in brackets [ ] at the end of each question or part question. You may use a calculator. You are reminded of the need for clear presentation in your answers. This document consists of 17 printed pages and 1 blank page. ANSWERS

2 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over 1(a) Propranolol was the first successful beta blocker developed to treat hypertension. It was developed by the British scientist James W. Black in the 1960s. In 1988, he was awarded the Nobel Prize in Medicine for this discovery. Propranolol acts as an antagonist to the -adrenergic receptors in the smooth muscle tissues of the heart. propranolol (i) Describe what is meant by the terms agonist and antagonist. [2] Answers: An agonist is a drug which mimics the natural ligand for a receptor.  An antagonist is a drug which docks well to the binding site, but does not cause the required change of shape of the receptor.  Propranol is sold as a racemate, a mixture of two isomers. The (R) -enantiomer is the beta-blocker for the heart and the (S)-enantiomer is a contraceptive. (ii) Suggest why propranolol is sold as a racemate , even though only one of its enantiomers is useful for treating hypertension. [1] Answers: The other enantiomer is not hazardous for the body and it is cheaper to produce the racemate. Unless the person taking the drug is a woman who wants to get pregnant, the racemate should not cause any problems.  (iii) Draw the two optical isomers of propranolol. [2] Answers: OH HO O C C O CH2 CH2NHCH(CH3)2 (CH3)2CHNHCH2 CH2 H H   (iv) Suggest a method to separate the two isomers. [2] Answers: Using chiral chromatography, where samples are separated or resolved by HPLC using a column packed with silica bonded to a chiral reagent such as cyclodextrin or hexahelicene to yield a chiral stationary phase. 

3 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over CH2Cl CH2Cl Cl OH OH H H Enantiomers present in the sample interact differently with the chiral stationary phase and this forms the basis of the separation.  or The second method is to react the racemic mixture with an optically active compound to form two diastereomers with slightly different physical  properties so that separation can be achieved.  Propranolol can be synthesised by the following two routes: (v) Suggest a mechanism for either one of the routes. [4] Answers: Route 1 OH  O: HO+ :O +   :NH O N O + HCl 

4 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over OH H H O O O O O: Route 2 HO: HO O:  ClCH2  + Cl  O N :NH  (b) Atenolol is another beta -blocker that was developed much later, in 1976, as a replacement for propranolol. Unlike propranolol, it does not pass through the blood-brain barrier easily thus avoiding various central nervous system side effects. atenolol (i) Outline the processes that are likely to occur when propranolol crosses the blood-brain barrier at physiological pH 7.4. [3] Answers: The amine group in propranolol can exist in both the ionised and unionised forms at pH 7.4. Both forms are in rapid equilibrium with each other. 

5 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over This allows the amines to interact strongly with binding sites on receptors, when in their ionised form, but also to pass through plasma membranes, in their unionised form.  (ii) Suggest why atenolol crosses the blood -brain barrier less easily than propranolol. [1] Answers: Atenolol has an extra amide group which is polar but not ionisable compared to propranolol and it is therefore more difficult for atenolol to pass through the hydrophobic cell membrane of the blood-brain barrier.  (c) Adrenaline (also known as epi nephrine) is a hormone and a neurotransmitter . Bucumolol is a -adrenergic blocking agent, like propranolol. adrenaline bucumolol The graphs below show the UV absorption spectra A and B of two solutions, one containing adrenaline and the other containing bucumolol , each at an equal concentration of 2.5 x 10 4 mol dm 3. The cells used had an optical path length (l) of 1.0 cm. Absorbance wavelength/nm A B

6 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over (i) Identify the two spectra, A and B, with appropriate reasons. [2] Answers:  Spectrum A belongs to bucumolol and spectrum B is that of adrenaline. There is higher degree of conjugation in bucumolol which causes the energy gap of   * to decrease shifting the UV absorption to longer wavelength.  (ii) A new sample containing a mixture of the two compounds was collected and analysed in a UV spectrophotometer at 280 nm and 300 nm. The absorbance at each wavelength was recorded below. Wavelength/nm Absorbance 280 0.88 300 0.42 Determine the concentrations of adrenaline and bucumolol in the new sample. [3] Answers: Assumption: At 300 nm, there is no absorption due to adrenaline. Therefore, [bucumolol] = 0.42 x 2.5 x 104 = 1.91 x 104 