NYJC H3 Chemistry P1

[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.

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] 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] (iii) Draw the two optical isomers of propranolol. [2] (iv) Suggest a method to separate the two isomers. [2] Propranolol can be synthesised by the following two routes: (v) Suggest a mechanism for either one of the routes. [4]

3 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over (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] (ii) Suggest why atenolol crosses the blood -brain barrier less easily than propranolol. [1] (c) Adrenaline (also known as epinephrine) 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.

4 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over Absorbance wavelength/nm (i) Identify the two spectra, A and B, with appropriate reasons. [2] (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] A B

5 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over 2(a) Salicin is an analgesic which can be isolated from willow bark. It is closely related in chemical make -up to aspirin and its action is also very similar to aspirin. salicin (i) Outline the different ways in which narcotic and non -narcotic analgesics relieve pain. [2] (ii) State one advantage and one disadvantage of using salicin instead of paracetamol. [2] (iii) Draw the Newman p rojection to illustrate the stable chair conformation of the six-membered ring in salicin. [1] (b) Compound D is another analgesic compound containing C, H, N and O. Its IR, 1H NMR and mass spectra are given below.

6 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over Deduce the molecular formula and the structural formula of compound D. Show your reasoning. [10] (c) Drugs such as celecoxib, rofecoxib and valdecoxib have been developed to be selective for the COX-2 isozyme, so that only the production of inflammatory prostaglandins is reduced. Such drugs would be better that aspirin as they do not cause any stomach bleeding by inhibiting COX-1. (M)179, 46 (M)180, 5

7 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over celecoxib rofecoxib valdecoxib A clinical trial was set up to evaluate how the analgesic activities of celecoxib, rofecoxib and valdecoxib compared to each other. Every 8 hours, hospital patients with chronic osteoarthritis pain were given, at random, capsules containing eithe r celecoxib, rofecoxib, rofecoxib or an inert compound X. The patients were asked to assess the pain they felt two hours after each administration, on a 4 -point scale (4 corresponding to severe pain; 3 for moderate pain; 2 for slight pain and 1 f or no pain at all). Sometimes the patients were not given any medication at all, but were still asked to assess the pain they felt after 2 hours. The results for 100 patients over 1 week were as follows. Substance Average pain score celecoxib 1.2 rofecoxib 2.4 valdecoxib 1.8 X 2.5 none 3.6 (i) What is the placebo effect? Explain how the above data illustrate this effect. [2] (ii) Use the above data to suggest which part of the three compounds shows greater effectiveness as an analgesic. [2] (iii) Two of the drugs, rofecoxib and valdecoxib, were withdrawn in 2004 and 2005 respectively because long term use led to an increased risk in heart attacks in patients. Suggest a reason why even after extensive clinical trials, a drug can to be withdrawn from the market. [1]

8 H3 Chemistry 9812/01 NYJC J2/14 PX [Turn over OH OH Br Br H H 3(a) Feist’s acid, C 6H6O4, was discovered by Feist in 1893, from a deceptively simple reaction by the action of hot, concentrated hydroxide on 3-bromo-5- ethoxy- carbonyl-4,6-dimethyl-2-pyrone. Based on IR spectra, it was assigned structure I below. CH3 CH2 HO2C CO2H HO2C CO2H Structure I Structure II Sixty years later, in 1950s, when the first NMR was invented, its structure was proved to be that of Structure II. (i) IR and NMR spectroscopy are used to provide structural information about organic compounds. Outline the principles underlying these two forms of spectroscopy. [4] (ii) Based on Structure I, what are the absorptions that would be present in the IR spectrum? [2] (iii) What evidence in the NMR spectrum would show that it is Structure II and not Structure I? [2] (iv) What types of stereoisomerism are present in Structure II? Explain your answer. [2] (v) Given that Feist’s acid is o ptically active, draw the correct stereoisomer of Feist’s acid. [1] (b) Which