b) Draw detailed structures of the substances below (1p per substance).

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1 Exam rganic Chemistry 2 (KD1100/3B1760) Thursday August 28, 2008, Allowed answering aid: molecular models Periodic system and tables of bond energies, pk a -values and MR-shifts are attached after the questions Total of 10 questions, each worth 10p (total 100p). Requirements: KD1100 3B1760 A p p B 80-89p C 70-79p p D 60-69p E 50-59p p Fx 45-49p F 0-44p U 0-50p A supplementary exam will be arranged for students with results of 45-49p. This exam will take place on Thursday September 11, 2008, at in the Erdtman-room, rganic Chemistry, Teknikringen 30, Level 7. o special registration necessary. Please note that the minimum requirement for the course have to be demonstrated in this case also. Answer every question on separate sheets to facilitate grading write name, programme and year on each sheet Motivate your answers, normally both text and figures are necessary Please observe that the questions are not necessarily organized in order of difficulty (question 10 is not essentially the most difficult!) Good luck! lof Ramström 1 a) ame the following substances with the used common names or according to IUPAC (1p per substance): b) Draw detailed structures of the substances below (1p per substance). - pyridine -,-dimethylformamide 1 (11)

2 c) Explain, in short, the following terms (1p per term): - reaction yield (explain how to calculate it) - homolytic cleavage - kinetic enolate d) Explain using orbital reasoning why nucleophilic attack at a carbonyl group occurs "slightly inclined from the back and from the top" (3p). 2 a) Draw a reaction diagram (energy vs. reaction coordinate) for a typical electrophilic aromatic substitution reaction. Indicate activation energies, transition state(s) and all structures (4p). b) Which of the structures below is the most reactive in an electrophilic aromatic substitution reaction Which one is the least reactive (2p) 2 Cl Et c) Specify where the next electrophilic aromatic substitution occurs for each of the structures in question b (4p). 3 a) The optimistic student squar wanted to synthesize substance 1 below. It was however not a great success and the resulting yield was very low. Explain, with detailed mechanisms, what is mainly produced and why squar's method did not work (4p). Cl AlCl 3 b) Describe how 1 can be synthesized using an alternative method from a similar starting material. o mechanisms are required, but indicate conditions and reagents/reactants (2p). c) Explain what is produced if 1 is treated with KMn 4 and the resulting product is heated (4p). 1 KMn 4 heat 1 2 (11)

3 4 a) Describe, using a detailed mechanism, how a typical aldol condensation occurs (4p). b) Explain what starting materials appear to have been used for each of the aldol condensation products below (4p). c) Which of the substances in question b cannot be produced in high yield in a typical aldol condensation Why (2p) 5 Complete the following reactions. o mechanisms required (2p per reaction). ClCr 3 - (water free environment) ac Et C 1) MeMgBr/ether 2) + / 2 heat aet Et 3 (11)

4 6 A compound with the molecular formula C shows the 1 -MR spectrum below: two singlets in the ratio 1:1. If the compound is treated with 0.1 equivalents ame (0.1 mole ame/mole compound), a new compound is produced with the molecular formula C after workup in acidic solution. The new substance can be isolated in up to 10% yield and shows the 1 -MR spectrum below (three singlets ratio 1,5:1:1,5). a) Explain what the substances are and indicate what signals belong to what protons (4,5p). b) Describe, with mechanism, what reaction occurred from addition of ame (4p). c) Why can a maximal yield of 10% be obtained in the reaction (1,5p) 4 (11)

5 7 Bakelite, a polymer prepared through the condensation of phenol and formaldehyde, is a crosslinked network polymer that was first developed by the Belgian chemist Leo Baekeland already in The material quickly became the first synthetic polymer that was produced in industrial scale, but was later made largely redundant by other plastics with better properties. a) Baekeland also discovered that is was possible to prepare linear, thermoplastic, polymers using the same method. Propose, using a detailed mechanism, how the synthesis of the linear polymer from p-cresol and formaldehyde proceeds under acid catalyzed conditions (6p). + + n p-cresol formaldehyde b) The linear polymer in question a can be cured (crosslinked) to the structure below. Propose what other reactants/reagents are needed for the reaction and describe with a detailed mechanism how the product is formed (4p). n m 8 a) The Stollé-synthesis is a well-known method to prepare so called oxindoles from anilines (Chem. Ber. 1913, 46, 3915). The reaction occurs in two steps from a suitable aniline and an acid chloride. Indicate the intermediate product 1 in the Stollé-synthesis below and describe, using detailed mechanisms including reagents/reactants, the reaction steps A-B (6p). + Cl Cl A 1 B -methylaniline oxindole-derivative b) Explain, using detailed mechanisms, how -methylaniline can be synthesized from benzene and appropriate reagents/reactants (3p). c) Explain with mechanism how the acid chloride in question a can be synthesized from an appropriate carboxylic acid (3p). 5 (11)

6 9 Transaminases are enzymes that catalyze the exchange between an amino acid and a keto acid using the coenzyme pyridoxal phosphate. The exchange occurs in several steps according to the sequence below (Ez = enzyme): R 1 R 3 R 2 Ez R 4 2 amino acid Ez- 2 R 1 R 3 R 2 R 4 Ez- 2 Ez- 3 + R 1 R 3 R 2 R 4 Ez- 2 Ez- 3 + R 1 R pyridoxamin phosphate 3 R R 4 keto acid 2-2 R 1 R 3 R 2 R 4 a) Is protonated pyridoxal phosphate aromatic Motivate your answer (2p). P 3 - Pyridoxal phosphate b) The first step is a so called transimination. Describe with a detailed mechanism how the following transimination occurs (4p): R Ez 2 R c) The following steps in the sequence are tautomerization and hydrolysis. Propose mechanisms for the following reaction steps (4p): B B + 6 (11)

7 10. Lyrica is a drug that was approved by the Medical Protection Agency (Läkemedelsverket) in 2004 for the treatment of peripheral and central neuropathic pain, and already one year at the world market (2006) the gross sale amounted to around seven billion SEK. Lyrica contains the active substance Pregabalin, which is a structural analog to the transmittor substance gamma-aminobutyric acid (GABA). The action mechanism for Pregabalin is not entirely known, but the substance decreases the release of several transmittor substances, including glutamate, norepinephrine and substance P. The substance Pregabalin was originally developed by R. B. Silverman (orthwestern University, USA), and the industrially used synthesis is shown below (Angew. Chem. Int. Ed. 2008, 47, 3500). Indicate the starting material 1 and describe with detailed mechanisms including reagents/reactants the reaction steps A-D (10p). Et 1 + Et Et A Et B Et 2 D C C C Et Chiral crystallization with S-mandelic acid 2 Pregabalin 2 gamma-aminobutyric acid (GABA) 7 (11)

8 8 (11)

9 Average Bond Strengths Bond Dissociation Energies (BDE) a Average Bond Dissociation Energies (kcal/mol) C F Si S Cl Br I a C b 73 c 86 d 116 e 72 f c 39 g 53 h a 86 d 53 h F e Si f S Cl Br I Average value. Approximately 103 kcal/mol for alchols and 119 kcal/mol for water b C=C 146 kcal/mol C C 200 kcal/mol c C= 147 kcal/mol C 213 kcal/mol d C= 176 kcal/mol for aldehydes and 179 kcal/mol for ketones e In CF 4 f C=Si 111 kcal/mol g = 111 kcal/mol 226 kcal/mol h In nitrites and nitrates Release of strain energy upon ring opening Cyclopropane 27 kcal/mol Cyclobutane 26 kcal/mol Epoxide 25 kcal/mol Aromatization energy Benzene 36 kcal/mol Pyridine 28 kcal/mol Delocalization of lone pair Carboxylic ester ~7 kcal/mol Carboxylic amide 17 kcal/mol ydrogen bonds 4-10 kcal/mol (usually) 9 (11)

10 SME APPRXIMATE pk a VALUES C -10 Strong Mineral Acids <0 F 3 C 12 (C) 3 C -5 Cl 14 C CF 3 C 2 R C R S 2 3 C R R R C R C R C C 25 RS 11 R 2 ~30 9 (C 6 5 ) 3 PC 3 35 RS R (I-Pr) 2 R C > R R (11)

11 CARACTERISTIC PRT CEMICAL SIFTS* Type of Proton Structure Chemical Shift, ppm Tetramethylsilane (TMS) (C 3 ) 4 Si 0 Cyclopropane C Primary R-C Secondary R 2 -C Tertiary R 3 -C 1-2 Amino R ydroxylic R-C- 1-6 Allylic C=C-C Esters -C-CR Acids -C-C 2-3 Carbonyl Compounds -C-C= 2-3 Acetylenic C C- 2-3 Benzylic Ar-C- 2-3 Iodides -C-I 2-4 Bromides -C-Br Alcohols -C- 3-4 Ethers -C-R 3-4 Chlorides -C-Cl 3-4 Esters RC-C Vinylic C=C- 4-6 Fluorides -C-F Phenolic Ar Aromatic Ar- 6-9 Aldehydic R-(-)C= 9-10 Enolic C=C Carboxylic RC * Fritt modiferad från: 11 (11)

1 a) Name the following substances with the used common names or according to IUPAC (4p): b) Draw detailed structures of the substances below.

1 a) Name the following substances with the used common names or according to IUPAC (4p): b) Draw detailed structures of the substances below. EGLIS VERSI Exam rganic Chemistry 2 (KD1100) Wednesday May 21, 2008, 08.00-13.00 Allowed answering aid: molecular models Periodic system and tables of bond energies, pk a -values and MR-shifts are attached