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Name _______________________ Page 1 F.05.215e3p1 I. (22 points) In the mid/late 1950s, mainly in Europe, a racemic mixture of thalidomide (see below) was prescribed to alleviate "morning sickness" in first trimester pregnant women. This was a tragic incident in the history of modern medicine because while the (R)-stereoisomer is an effective sedative, the (S)-stereoisomer turned out to be a potent mutagen in foetuses, and until this was tracked down there were thousands of babies born with severe birth defects. A naive response to this discovery was "We should separate the enantiomers, purify the (R)-isomer and only use it as the drug." The problem with this solution could be identified with a simple experiment: in acidic solutions, pure samples of thalidomide undergo mutarotation. As indicated below, solutions of pure samples of either the (R) or (S)-stereoisomer, when placed in mild, aqueous acid solution, becomes optically inactive solution of thalidomide. O O N N H O O O O N O N H H optically inactive solution of thalidomide (R)-(+)-thalidomide optical rotation = +63° 2% H SO /H O 2 4 2 room temp H (S)-(-)-thalidomide optical rotation = -63° optically inactive solution of thalidomide 2% H2SO4/H2O room temp O (a) Explain, in a few words, the observation of mutarotation to an optically inactive solution of thalidomide in terms of the mechanism that must be taking place. An optically inactive solution of thalidimode means a racemic mixture (1:1 R:S), so the molecule is undergoing a change that equilibrates the configuration of the stereocenter. basic idea about racemization 4 (b) Using H3O+/H2O as your Bronsted acid/base pair, provide the curved arrow mechanism for the acid-catalyzed process that explains the observation of mutarotation, starting with the (R)-isomer. O N O H O O N N H O H2O O H OH2 N H O O mech = 2 intermed = 2 N O H O O O N O H H2O H O O N N H + N H O H O H H O N H O 14 O (c) Why are the results of these mutarotation experiments enough to be skeptical that just prescribing the (R)-thalidomide to pregnant women is a good idea? racemization in acid would mean that the molecule cound also undergo racemization, and so the bad (S) form would be formed basic idea about the S isomer forming 4 Name _______________________ Page 2 F.05.215e3p2 II. (33 points) A. When the !-form of the following carbohydrate derivative (Compound A) is treated with methanol in acid, the "-form of the glycoside (Compound B) is observed to be the major product due to the anomeric effect, but when the same starting material is treated with iodomethane and sodium hydride, the !-glycoside (Compound C) is formed. H3CO O H CH3OH H3CO H3CO O O cat. H2SO4 H3CO Compound B OCH3 H CH I 3 H Compound A H3CO O OCH3 NaH H CO 3 Compound C H (a) Draw the structure of the key intermediate (b) Explain, briefly, using words and drawings, in the conversation of Compound A to why the formation of Compound C takes Compound B that explains its ability to place with no change in the configuration at undergo inversion of configuration? the anomeric center. deprotonation of the OH both does not impact the stereochemistry of the CO bond H3CO O main idea = 2 H3CO O relevant pic = 2 H3CO O H H3CO open shell res form OK B. (a) Using the Fischer projection, draw the structure for L-histidine that will be in greatest proportion in a solution of pH = 3.9. See front cover for pKa values wrong O O imidazole = -2 H3N H connect = 3 prot state = 2 H N H 4 (b) Galactose is the C-4 epimer of glucose. Draw the structure for "-L-galactopyranose. epi-glu = 2 alpha = 1 L=2 HO O OH HO N H OH HO 4 (c) Draw the open chain (Fischer) form of an aldotetrose that becomes optically inactive when treated with sodium borohydride and acid. O H OR O H H H H OH HO H OH HO CH2OH CH2OH 5 no partial 5 (d) Using the Fischer projection, (e) Draw the amphipathic (amphiphilic) molecule: draw the structure for the methyl ammonium hexadecanoate ester of L-proline that will be in greatest proportion in a solution O of pH = 5. O H2N NH4 OCH3 H connnectivity = 3 correct protonation = 2 O ammonium = 2; hexadecanoate = 3 must be ionic! 5 5 5 Name _______________________ Page 3 F.05.215e3p3 III. (31 points) A. You will recall, perhaps, that when alkenes such as styrene (Compound D) are treated with OsO4 or related oxidizing agents, a 1,2-diol is formed. When phenylacetylene (Compound E) is treated with oxidizing agents such as OsO4, the corresponding addition reaction product is not observed; instead it is proposed that the initial addition reaction product, which is an ene-diol, undergoes an isomerization reaction to give a mixture of two different C8H8O2 isomers.What are these two isomers? Compound D Compound E can be in either box OH O OH O + OH H OH ene-diol intermediate no partial no partial 3 3 B. The two most acidic protons in ascorbic acid (also known as Vitamin C) have pKa values of 4.17 and 11.59. Which of the protons in ascorbic acid corresponds to the most acidic one, and why? circle the use words and drawings to explain H most acidic H best resonance O O H H proton stability in O O O O conjugate base H H O O H O O O O O O words 3 O O pix 3 O O H H H no partial 6 2 O C. C H3N O (1) H O (H3C)3C (2) H3O which amino acid is this? use its abbreviation as your answer D. D-Fructose is the ketose derived from Dglucose; show the Fischer projections for the pair of epimeric alcohols that result from the sodium borohydride reduction of D-fructose. O C C(CH3)3 O with (CH3CH2)3N Cl CH2Ph O O C HN connectivity = 3 state of protonation 2 Phe OH C H CH2Ph 5 4 can be in either box CH2OH CH2OH H HO OH HO H H HO H H OH H OH H OH H OH CH2OH 4 CH2OH OK as long as true epimer 4 Name _______________________ Page 4 F.05.215e3p4 IV. (18 points) A. An acid-catalyzed aldol reaction is observed when dihydroxyacetone is combined with glyceraldehyde. O CH2OH C H H CH2OH C C O OH CH2OH O acid catalyst H2SO4 CH2OH dihydroxyacetone H C OH H C OH H mixture of stereoisomers here OH CH2OH (a) Using HB as a Bronsted acid and B as its conjugate base, show the step-wise mechanism for the formation of the nucleophilic form of dihydroxyacetone required for this reaction. CH2OH C CH2OH B H C O CH2OH B- O H C H nucleophilic form CH2OH H C O mech 2 intermed 2 H mech 2 OH 6 H C 2 OH (b) Given the prior formation of the nucleophilic form of dihydroxyacetone, provide the complete step-wise mechanism for the reaction between dihydroxyacetone and glyceraldehyde. O H CH2OH H C H B C OH CH2OH H O H C H H C H O CH2OH OH OH CH2OH prot mech = 2 prot ald = 2 addn mech = 2 prot prod = 2 deprot mech = 2 PLEASE NOTE: THIS IS EXACTLY THE SAME SET-UP AND PROBLEM AS PAGE V ON THE SECOND EXAM H C O H C OH H C H B- OH OH CH2OH CH2OH C O H C OH H C OH H OH CH2OH 10 Name _______________________ Page 5 F.05.215e3p5 V. (16 points) A. An interesting, yet complex, molecule was recently prepared (JOC 2005, 70, 7585). For the sake of clarity, the molecule is represented according to some of its properties rather than its actual structure. Molecular Shape in organic Molecular Shape in water THIS IS A COMPLEX MOLECULAR solvent FRAGMENT: ONE SIDE OF IT IS HYDROPHOBIC WHILE THE OTHER SIDE IS HYDROPHILIC hydrophobic side hydrophilic side FOUR OF THESE MOLECULAR UNITS HAVE BEEN ATTACHED TO A CIRCULAR MOLECULAR FRAMEWORK (shown on the right). O O OO NH NH NHHN O O OO NH NH NHHN O W In an organic solvent, the molecule takes on the shape represented by Structure O, where the hydrophilic groups gather together and hydrogen bond to each other. In water, the molecule spontaneously takes on the shape suggested by Structure W. Describe briefly why the spontaneous reorganization in molecular structure takes place is thermodynamically rational when this molecule is placed in water. the hydrophobic effect: the hydrophobic portions of the molecule turn in toward each other in order to minimize the surface contact between these parts of the molecule with water... the reason for this is that water at a hydrophobic surface has a lower entropy, so sheding these water molecules into the bulk of the solvent increases the entropy of the system description of hydrophobic effect/phenomenon = 3; impact on entropy = 3 B. Draw the Fischer projection for the open chain form of D-idose, an aldohexose whose IUPAC name is (2S, 3R, 4S, 5R)-2,3,4,5,6-pentahydroxyhexanal. O 6 H C. The titration curve for L-lysine is shown below. Provide the main HO H structures in equilibrium at the point indicated below. H OH 12 HO H 11 H OH 10 9 CH2OH 8 4 no partial pH 7 6 can be either O O O 5 O box 4 H3N H H3N H 3 CH2CH2CH2CH2NH3 CH2CH2CH2CH2NH2 2 3 3 1 OK IF THE DEPROTONATION IS SHOWN FOR THE OTHER 0 1 2 3 0.5 1.5 2.5 N GROUP INSTEAD equivalents of based added