Lectures 13 & 14 Key, with contributions from Palleros CHEM 109

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1 Lectures & Key, with contributions from alleros CEM 09.Build the nucleosides (sugar and base) & nucleotides (sugar, base, and phosphate). ucleobase ucleoside (D) - deoxyribose ucleotide (R) - ribose denine - - uanine - - Cytosine Thymine - - X Uracil X - -

2 Lectures & Key, with contributions from alleros CEM 09. eterocycles in drugs (refer to table in Lecture notes) a) Loratadine b) Rosuvastatin pyridine pyrimidine piperidine C S C c) torvastatin d) Cimetidine pyrrole S C imidazole C e) Ciprofloxacin You may not recognize the quinoline ring system in the structure on the left, but it s easier to see it in the resonance structure on the right. ucleic cids Components dditional roblems. nswers quinoline Daniel alleros piperazine piperazine f) Tioconazole imidazole S thiophene roblem a) yrrole (pk a = 7.) is more acidic than pyrrolidine (pk a ) because the anion of pyrrole is more stable than the anion of pyrrolidine. The higher acidity of pyrrole is due to the sp hybridization of the ; sp hybridized atoms have more s-character, hold electrons tighter and, in general, are more electronegative and more tolerant of negative charges than sp hybridized atoms and, thus, yield more stable anions. yrrole

3 Lectures & Key, with contributions from alleros CEM 09. Basicity in heterocycles a) yrrole (pk a = 7.) is more acidic than pyrrolidine (pk a ) because the anion of pyrrole is more stable than the anion of pyrrolidine. The higher acidity of pyrrole is due to the sp hybridization of the ; sp hybridized atoms have more s-character, hold electrons tighter and, in general, are more electronegative and more tolerant of negative charges than sp hybridized atoms and, thus, yield more stable anions. yrrole + pk a = yrrolidine sp + pk a! + + sp b) The conjugate acid of pyrrole (pk a = 0.) is more acidic than the conjugate acid of pyrrolidine (pk a =.) because pyrrole is an aromatic compound while its conjugate acid is not. Deprotonation of the conjugate acid of pyrrole restores the aromaticity to the pyrrole ring with a significant increase in stability. Such gain in stability does not occur in the deprotonation of pyrrolidine, an aliphatic amine. conjugate acid of pyrrole: pk a = 0. + aromatic + conjugate acid of pyrrolidine: + + pk a =. aliphatic c) yrimidine (pk a conj. acid =.; pk b =.7) is less basic than pyridine (pk a conj. acid =.; pk b = 8.7) because the second atom in pyrimidine is electronwithdrawing and destabilizes the positively charged conjugate acid. It can also be explained by saying that the electron-withdrawing effect of the second makes the electron pair less prone to protonation. pyrimidine: + + pk b =.7 pyridine: + + pk b = 8.7 less stable than

4 Lectures & Key, with contributions from alleros CEM 09 con td d) yridine is less basic than piperidine because in pyridine the lone electron pair is on an sp hybridized orbital which, having more s-character, is more electronegative and more difficult to get protonated than the electron pair in piperidine which is located on an sp orbital. pyridine piperidine sp pk b = 8.7 pk b =.8 sp e) 7 in purine is less basic than in imidazole because the pyrimidine ring, present in purine but not in imidazole, due to its two electron-withdrawing atoms takes electron density away from the adjacent ring, making it less prone to protonation. urine Imidazole less basic than imidazole 7 9 take electron density away from adjacent ring f) The on purine s 9 is more acidic (pk a = 8.9) than the on imidazole s (pk a =.), because the conjugate base of purine (anion on 9) is more stabilized than the conjugate base of imidazole (anion on ) due to the presence of the electronwithdrawing pyrimidine ring. 7 urine anion 9 take electron density away from adjacent ring Imidazole anion g) Both heterocycles have two atoms. In pyrimidine, a π-deficient ring, both atoms with their electron pairs outside the ring, are electron withdrawing and they mutually decrease their electron densities, making themselves less basic. In imidazole, on the other hand, with an electron pair inside the ring, donates electron density and increases the electron density on the other nitrogen,, making it more basic. pk a conj. acid = 6.9; pk b = 7.0 Imidazole electron donor pk a conj. acid =. pk b =.7 both are e-withdrawing yrimidine

5 electrons and, thus, are aromatic but these structures involve charge separation between atoms of identical electronegativity (two ), which has a high energy cost and, therefore, do not Lectures contribute much & Key, to the with stability contributions of the from molecule. alleros Experimentally it was CEM found that 09 only tautomers I and II occur in measurable amounts in water (both in similar amounts). m. Risperidone III less basic: sp hybridized nonbasic: amide IV roblem 0 C less basic: sp hybridized most basic: aliphatic amine (sp hybridized ) deamination LECTURE W KEY. Draw structures for four different enol forms of uracil. adenine hypoxanthine I major tautomer roblem roblem 9 guanine II deamination III. ropose a mechanism for the deamination of cytosine catalyzed by acid (+ charges): IV xanthine minor tautomers V + proton transfer cytosine - otice that in each of them the is attached to a different. Tautomers I and II are more stable than tautomers III and IV because in I and II each ring has 6 π electrons and is fully aromatic. In the resonance forms shown above for tautomers III and IV each ring does not have a ückel number of electrons (the pyrimidine + has 7 and the imidazole has π electrons), and therefore, each one separately cannot be considered aromatic, although the whole molecule is aromatic because it has 0 π electrons). There are other uracil resonance forms for tautomers III and IV (shown below) in which each ring has 6 π **Two arrows missing in key above (arrows moving e- back to in st and last steps)

6 Lectures & Key, with contributions from alleros CEM 09. Mutation of methyl cytosine. t p 7., the main species in equilibrium are - (major) and - (minor). The dibasic anion is the more dominant species because p 7. is closer to its pk a (7.).. Draw the -Bonding patterns for both -T and -C. ractice this a few times on your own without looking at the key (structures of bases will be given on the final). 6

7 Lectures & Key, with contributions from alleros CEM Dinucleotide synthesis denosine B: uanosine entacoordinate phosphate intermediate Dinucleotide **It is still K to use the lazy S mechanism on phosphorus, I just didn t want you to forget that it is an abbreviation! 7. Dinucleotide hydrolysis entacoordinate phosphate intermediate denosine - - :B - - Dinucleotide - - B: uanosine 7