Theophylline (TH), the structure of which is presented below, is a bronchial-dilator used for the treatment of asthma.

Transcription

1 1 EXAM SCIETIIC CULTURE CEMISTRY PRBLEM 1: Theophylline (T), the structure of which is presented below, is a bronchial-dilator used for the treatment of asthma. 3 C Structural study and acid-base properties C Indicate for the nitrogen atoms 7 and 9 their hybridization state, the nature of the orbital containing the non-bonding electron lone pair, and specify whether this orbital is in the same plane as the molecule or out of the plane Write another form of the theophylline which allows identifying its aromatic character and specify the number of electrons involved in the aromaticity. Theophylline (T) behaves like a weak acid. The acid-base couple (T/T - ) is characterized by a pk a1 of Present the structure of the conjugated base of theophylline (T - ) and write another form showing the most important delocalisation of the electrons. Theophylline is administered as an ammonium salt of theophylline, the cation is symbolized by R 3. The pk a2 value is given: pk a2 (R 3 /R 2 ) = In water, theophylline is less soluble than its ammonium salt. Explain What is the p of a solution of the ammonium salt of theophylline at a concentration of 10-1 mol.l -1? Theophylline is also a ligand for metal ions, such as copper. In the presence of a salen ligand a neutral complex is formed with copper in a II oxidation state: C C 2 7 Cu salen complex Write the electronic configuration of the Cu 2 ion (Cu: Z = 29) ow many electrons can be found in the valence shell of copper in this complex?

2 1.1.8 Even though the 18 electron rule is not verified, such a complex is stable. Propose an explanation xidation of theophylline The oxidation of theophylline (T) by dissolved dioxygen in the presence of the enzyme xanthine oxidase, results in the formation of 1,3-dimethyluric acid (U) and hydrogen peroxide ( 2 2 ). This reaction was studied at 300 K and implies the couple U / T. The redox equation is given below: 3 C 3 C 2 2 e - 2 C 3 C 3 1,3-dimethylurique acid (U) Theophylline (T) ,3-dimethyluric acid (U) is a weak acid with a pk a (U/U ) of 5.4. Which form of this acid is predominant at physiological p? Write the redox equation of the couple (U /T) and explicit the potential E 1 of the couple (U /T) as a function of its standard potential E 1 and the concentrations of [ ], [U ] and [T]. ow does this expression change when E 1 is introduced into the equation? E 1 corresponds to the standard biological potential of the couple (U /T) with all the concentrations equal to their standard value except for the proton concentration which equals to 10-7 M (so that the p is fixed at 7) Write the equation of the redox couple ( 2 / 2 2 ) and explicit the potential E 2 of the couple ( 2 / 2 2 ) as a function of E 2 (standard biological potential of the couple 2 / 2 2 ) and the concentrations of [ 2 ] and [ 2 2 ] Write the reaction that occurs spontaneously under these standard biological conditions beween the couples (U /T) and ( 2 / 2 2 ) knowing that E 1 = - 0,36 V and E 2 = 0,3 V. Justify you answer. 1.3 Ribofuranosyl theophylline Ribofuranosyl theophylline 5 was synthesized in order to evaluate its antiviral properties. This synthesis was carried out starting from D-ribose 1 and 4,5-diamino-1,3-diméthyluracile 2 : C 3 C 3 (a) C ' 1' 2 4' 2' 2 5 C 3 3' C C 3 C 2 5 (b) 3 C 2 5 C 2 C 3 2 C 2 5 C 3 C 2 4 5

3 D-ribose 1 exists in aqueous solution as a cyclic form and also in very small quantities as an open form Write the mechanism of the reaction that transforms the cyclic form into the open form in an acidic medium Treatment of D-ribose 1 by 4,5-diamino-1,3-diméthyluracile 2 results in the formation of 3 according to reaction (a). Write the mechanism of the reaction (a), catalyzed by a weak acid A, which transforms the open form of D-ribose into compound The amine function of 2 carried by carbon 4 is less nucleophilic than the one carried by carbon 5. Represent another mesomeric form of 2 which allows justifying this difference in nucleophilicity. When compound 3 is treated with diethoxymethyl acetate 4, ribofuranosyl théophylline 5 is formed according to reaction (b). This transformation can be interpreted under acidic catalytic conditions as a succession of four steps, denoted as (i), (ii), (iii) and (iv). or these steps, compounds 3 and 5, and the intermediates are represented by a simplified formula Propose a mechanism for step (i) below: (i) 3 C C 2 5 C 3 -C 2 C Specify the electrophilic or nucleophilic behavior of the intermediate A and propose a mechanism for step (ii) below: 4 C C 2 5 (ii) C 2 5 C 2 C 2 5 C 2 5 C 2 5 A C C C 2 5 A 3 B Propose a mechanism for the following step (iii) and represent the monocyclic reaction intermediate C: (iii) C 2 5 C 2 5 B What is the reaction type of the following step (iv)? C 2 5 C C 2 5 C 2 5 D (iv) C 2 5 C 2 5 D 5

4 4 ÉPREUVE DE CULTURE SCIETIIQUE CIMIE PRBLEM 2 : This exercise examines part of the vernolepin synthesis reported in 1976 by the Danishefsky s group. 2.1 In a first step, one considers the following sequence of reactions: What is the name of the reaction leading to the formation of the bicyclic molecule 3? Indicate in the formula of the product 3 which new σ C-C bonds have been formed during this step The following diagram displays the overlap of the molecular orbitals, which are involved in the formation of the product 3. Make an interpretation of the diagram. Indicate which overlap drives the cyclization reaction according to respective values of the energy differences E 1 and E Solubilized in an acidic aqueous solvent, the compound 3 yields the ketoester 4. Propose a mechanism to account for this conversion. Which side-products are formed during this conversion? 2.2 Two subsequent transformations are performed: Draw the structure of the product 5 associated to the formula C The conversion of the compound 5 into the product 6 is performed under kinetic control. What is the corresponding information? What is the other regime of control which is often used in organic chemistry?

5 2.2.3 Propose a mechanism for the formation of the product 6 from the compound 5. Which explanation could you propose to account for the formation of only one stereoisomer during this step? 2.3 The compound 6 is treated by the 1,8-diazabicycloundec-7-ene (DBU), which acts as a base: What is the most basic site in the DBU molecule? Justify What is a priori the mechanism involved in the conversion of the halogenated derivative 6 into the ethylenic derivative 7? Justify your answer and write the corresponding mechanism. 2.4 Two oxidation steps follow: Which reagents would you propose to achieve both conversions from 7 to 8, and from 8 to 9? 2.5 The carboxylic acid 9 is treated by diazomethane C 2 2 to yield the methyl ester 10: Draw the Lewis structure of diazomethane Propose a mechanism to account for the conversion of 9 into The compound 10 is eventually converted into the aldehyde 11 by a series of transformations which will not be examined. Part of the investigated synthesis is finally achieved by the formation of the ethylenic derivative 12 after reaction of 11 with the reagent Ph 3 PC Draw the Lewis structure of the reagent Ph 3 PC Propose a mechanism accounting for the conversion of 11 into 12.

6 6 EXAM SCIETIIC CULTURE CEMISTRY PRBLEM 3: 3.1. The glyphosate (GP), which is the main component in Roundup, and 2- luorophosphoenolpyruvate (PEP) are both molecules that block the biosynthesis of aromatic amino acids. pka 4 = 10,6 pka 3 = 2,2 2 C GP P 3 2 pka 1 = 0,7 pka 2 = 5,9 1 PEP -P 3 2 C What is the state of protonation of GP at physiological p (p = 7)? Write the Lewis structures of the C 2 and P 3 2 groups Does the presence of the nitrogen atom in GP have an influence on the acidity of the functional group P 3 2 (compared to C 3 -P 3 2 ) and on the functional group C 2 (compared to C 3 C 2 )? Explain your reasoning Which is the configuration, E or Z, of the molecule PEP? During the inhibition PEP is protonated and forms a carbocationic intermediate at carbone 1. Represent this carbocation and compare its stability to the one of the same carbocation formed from PEP : -P C PEP C 2 Glyphosate (GP) is an inhibitor of the enzyme 5-enolpyruvoyl-shikimate-3-phosphate synthetase (denoted E). Thermodynamic values, such as the dissociation constant K d and the standard biological enthalpie r were determined for the dissociation reaction of the enzyme-inhibitor complex [E-GP] and the enzyme-substrate-inhibitor complex [E-S-GP]. K d and r correspond to the dissociation constant and the reaction enthalpy with all the concentrations equal to their standard value except for the proton concentration which equals to 10-7 M (so that the p is fixed at 7). (1) [E-GP] E GP K d1 = r 1 = 55 kj.mol -1 (2) [E-S-GP] [E-S] GP K d2 = Does a comparison of the values K d1 and K d2 allow to deduce whether GP is more strongly fixed to the enzyme in the absence or in the presence of substrate S? Does the value of r 1 give any information about the interactions between the active site of the enzyme and the inhibitor? Explain your reasoning.

7 3.2. We are now interested in the synthesis of a precursor of the inhibitor PEP starting from ethyl difluoroacetate C 2 -C 2 and diethyl oxalate Et 2 C-C 2 Et. The first step is a Claisen condensation in ethanol in the presence of sodium ethanolate C 3 -C 2 -, a (Et, a ). The reaction equation is shown below: 7 C 2 -C 2 Et Et 2 C-C 2 Et Propose a mechanism for this reaction. Et, a Et 2 C-C 2 -C-C 2 Et Et Would the same diester be obtained if sodium ethanolate would be replaced by sodium methanolate (C 3 -, a )? Justify your answer. The second step of the synthesis is the acidic hydrolysis of the diester in water according to the reaction below: Cl Et 2 C-C 2 -C-C 2 Et 2 C-C 2 -C-C 2 2 Et 2 We will consider the hydrolysis reaction of a monoester RC 2 Et under the same conditions. The constant k corresponds to the apparent rate constant of the water addition step to the protonated ester R-(C 2 ) Et Knowing that the rate determining step is the addition of the nucleophile, write the rate law v of the reaction as a function of k and K a, where K a is the acidity constant of the couple R-(C 2 ) Et/R- C 2 Et. Water can react with the diacid 1 to form a hydrate according to the reaction (1): 2 (1) 1 In the general case, represented by the hydration of acetone 3 C-C-C 3 in the reaction equation (2), the equilibrium is in favour of the ketone: 2 (2) 3 C C 3 3 C C What is the influence of the inductive effects of fluoride on the reaction rate of the water addition to the carbonyl of 1 compared to the one of acetone? Explain your reasoning. The diacid 1 is then decarboxylated in basic medium. The reaction mixture is then again acidified in order to form compound 2. Since the ketone is in equilibrium with the hydrated form (see question 3.2.4), the decarboxylation can be envisaged either starting from the hydrated molecule (mechanism A) or starting from the ketone (mechanism B).

8 8 mécanisme A C C C 2 C 2 C 2 C 2 C C mécanisme B C C C 2 2 C 3 C 2 2 C C The first step of the mechanism A is an anti unimolecular elimination. Would the mechanism A always be possible independent of the conformation of the hydrated form of compound 1? Justify briefly Would a decarboxylation also be possible for the second carboxylate function C - 2? Justify. The compound 2 C-C-C 2, 2, is then placed into methanol, C 3 -, in the presence of a strong acid. Three products are obtained under these conditions: C 3 3 C C 3 2 C CC 3 2 C CC 3 2 C CC Is the solution obtained in the end containing 3, 4 and 5 optically active? Justify your answer Would the formation of these three products be equally observed if the reaction were performed in basic medium? Justify your answer.