DHS H3 CHEM ANSWERS

1 © DHS 2011 9812/01 [Turn over Answer any five questions. 1 (a) 1H NMR is a common analytical technique used to determine the molecular structures of various compounds. (i) Outline the basic working principles of NMR. [2] Nucleus of proton spins and generates a magnetic moment [0.5]. When a magnetic field is applied, the magnetic moment aligns with or against the applied magnetic field. To switch from the lower energy spin state that aligns with the applied field to the higher energy state that aligns against the applied field[0.5], radio–frequency radiation is absorbed [0.5]. The exact frequency of absorption depends on the chemical environment of the proton[0.5]. An unknown compound A, C 5H10O2, was synthesised in the laboratory. It is used to manufacture various propionates which are used as anti–bacterial agents. Its MS, IR and 1H NMR spectra data given below. (i) Deduce the structure of compound A, giving your reasoning. [8]

2 © DHS 2011 9812/01 [Turn over [1] absorption bond 1740 C=O 1200 C–O  Absence of peak at 3230 to 3500 cm–1 suggests absence of O–H stretch  No alcohol [1]  The presence of a C–O (strong and broad) at 1200 cm–1 and C=O at 1740 cm–1 confirm the identity of an ester functional group. [1] chemical shift /ppm splitting pattern No. of adjacent protons relative peak area group responsible 1.15 triplet 2 3 –CH 3 (a) [1] 1.25 triplet 2 3 –CH 3 (b) [1] 2.30 quartet 3 2 –CH 2CO– (adjacent to a –CO– and –CH 3) [1] 4.15 quartet 3 2 –OCH 2– (adjacent to a –CO– and –CH3) [1] m/e species 102 (C 5H10O2)+ [1] 57 (CH 3CH2CO)+ 29 (CH 3CH2)+

3 © DHS 2011 9812/01 [Turn over (b) Opium is the air–dried milky exudate, or latex, obtained by incising the unripe capsules of the opium poppy Papaver somniferum. It contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. Morphine is also used as a narcotic analgesic and for the treatment of dry cough and diahorrea. morphine (i) Explain the term narcotic analgesic, using morphine as an example. [1] Narcotic analgesic, like morphine, is a substance that depresses the activity of the central nervous system resulting in pain relief. (ii) Narcotic and non–narcotic analgesics act differently to prevent pain. Briefly outline the modes of action of non–narcotic analgesics. [1] Non–narcotic analgesics work by inhibiting the cox enzyme and reducing the biosynthesis of prostaglandins. c (iii) Assign the stereochemical configuration about the chiral carbon atoms 1, 2 and 3. [2]     All correct [2], 1 correct [0.5], 2 correct [1] (c) Many drugs, like morphine, contain the tetrahydrofuran ring in their structures. Shown below is the puckered conformation of tetrahydrofuran. H O H H H H H H H tetrahydrofuran HO O OH R R S N CH3 H 1 2 3

4 © DHS 2011 9812/01 [Turn over (i) Suggest a simple synthetic pathway for the formation of the cyclic ether, C, from compound B. State clearly all reagents and conditions required for the proposed steps of the synthesis. [4]   (ii) Draw two different conformers of cyclic ether, C, showing the positioning of the substituent on the ring. State which of the two conformers is more stable, giving your reasoning. [2] H O H H H H H H H O H C H H H H OH H HHC H HO H conformer I conformer II   Each [0.5]  Conformer II is more stable [0.5] because the bulky substituent at the axial position in conformer I will experience 1,3–diaxial interaction [0.5] whereas in conformer II, the substituent at equatorial position experiences less repulsion. [Total: 20] Max [4], minus [0.5] for each wrong reagent/condition or intermediate.

5 © DHS 2011 9812/01 [Turn over 2(a) Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Modafinil, methylphenidate and ampakine are stimulant drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of various disorders. The structures of all three compounds are shown below. A mixture of these compounds can be analysed by reversed phase column HPLC. The compounds are detected as they emerge from the column using UV spectroscopy. (i) Predict the order at which the compounds will be eluted and explain the difference in their retention times. Order of elution: Ampakine, methylphenidate followed by modafinil. [0.5] Ampakine molecule is most polar[0.5] as it has a polar carboxylic acid group/ two hydroxyl groups/ more polar groups/ more O and N atoms [0.5] than methylphenidate and modafinil molecules. Hence more effective hydrogen bonding can take place between the sample and the polar solvent mobile phase[1]. Hence ampakine is eluted earliest. Modafinil will be eluted last due to its relatively larger non–polarity [0.5] because of the presence of two aromatic (or cyclic) ring [0.5] in the molecule compared to methylphenidate. (ii) Explain why the three compounds may be detected using UV, and state what happens in their molecules when UV radiation is absorbed. All the three compounds are chromophores as they contain either isolated bond, and/or a conjugated system of double bonds[0.5]. Hence,   *, n * and n  * transitions which corresponds to the UV/vis region are possible [0.5]. When the photon is absorbed by a molecule, an electron gains the photon’s energy and is promoted to a higher electronic level. [0.5] [5] Some stimulants exert their effects by mimicking the action of the neurotransmitter acetylcholine. O N+ O acetylcholine 3 2   (iii) Draw and label the Newman projections (along the C2–C3 bond) to show the six conformations of acetylcholine. Sketch a potential energy profile diagram to illustrate the relative stability of these conformers. [4]

6 © DHS 2011 9812/01 [Turn over    I (most unstable eclipsed) II (gauche) III (eclipsed)    IV (anti–staggered) V (eclipsed) VI (gauche) Correct projections and labellings max [2], minus [0.5] for each wrong projection.          Correct diagram with labelling and axes, max [2], minus [0.5] for each mistake.                                                                             Rotation 0 60 120 180 240 300 360 I II III IV V VI I OOCCH3  H  H H  H  OOCCH3 H  H H      H  N+(CH3)3 H3CCOO HH   (CH3)3 +N H N+(CH3)3H    H H  H3CCOO  H H  H  H  H3CCOO OOCCH3 N+(CH3)3 HH H H (CH3)3 +N  N+(CH3)3  H H  Potential energy

7 © DHS 2011 9812/01 [Turn over (b) Rohypnol, a benzodiazepine derivative, is marketed as a highly potent hypnotic drug with sedative properties. It binds to  the  gamma–aminobutyric acid–A (GABAA) receptors in the central nervous system and inhibits neurotransmission.     (i) Explain how agonists and antagonists differ in their interactions with receptors. [2] Agonists compete for the receptor site, causing the necessary change in shape there. [1] Antagonists block the site without causing the necessary change in shape. [1] (ii) Suggest with reason if rohypnol is more likely to be an agonist or antagonist. [1] Antagonist. [0.5] Rohypnol has different structural features compared to the natural ligand, GABA, [0.5] and it contains larger hydrophobic groups to increase its binding strength. The synthesis of Rohypnol from compound D is as outlined be