Lecture2: 123.312

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An introduction to alcohols, their uses and substitution reactions; conversion to go leaving groups.

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Lecture2: 123.312

  1. 1. FUNCTIONALGROUP 123.312 most nucleophiles also act as bases INTERCONVERSIONS functional group previously we had seen CHAPTER3 that alcohols can rarely undergo interconversions sn2 substitution Nuc O Nuc H O R CHAPTER three H R functional group interconversions & alcohols E 1 2 3 Text Solution one: so the general scheme is... sulfonate esters... functional O O R Nuc O O Nuc group O O R S 1 R OH R S 1 O R S 1 interconversion O R O R readily formed & readily substituted ©pal berge@flickr 4 5 6 sulfonates are good leaving groups because... p-toluenesulfonate (tosyl) methanesulfonate (mesyl) OO OO S S O O O O O O S 1 R O R O not as acidic; not as S 1 S 1 most common. good a leaving group . O R O R O R good balance of but small size is an O reactivity & usability O advantage R Ts R Ms resonance/ delocalisation stabilise negative charge pKa = ~ –6 pKa = –2.6 7 8 9
  2. 2. trifluoromethanesulfonate superacids (triflate) acid with an acidity greater than 100% pure sulfuric acid OO F F S F F F how do we prepare R O F incredible leaving H Sb F sulfonate esters ? O group; very unstable; very acidic; very useful F R Tf if you are careful F about 2x1019 about 1000 times stronger than pKa = –14 more acidic than H2so4 H2SO4 ©mali mish@flickr 10 11 12 standard substitution... and the mechanism... and the mechanism... OO HCl OO HCl OO HCl H OH O O pyridine N H OH O O pyridine N H OH O O pyridine N H O S H O S H O S S S S R1 R2 Cl Tol Tol R1 R2 Cl Tol Tol R1 R2 Cl Tol Tol R1 R2 R1 R2 R1 R2 H O O H OO N H O O remember, sulfur His OO N H O S Cl H O S H O S Cl in the third row O S H Tol Tol Tol so can have 18 Tol R1 R2 R1 R2 R1 R2 valence electrons R2 R1 13 14 15 standard substitution... Please Note: most common mistake mesylate is not formed by a is the believe that pyridine can standard substitution... deprotonate an alcohol...look OO HCl at the pka, it can’t! HCl OO H OH O O pyridine N N H H OH O O pyridine N X H O S H O H H O N H O S S S R1 R2 Cl Tol Tol R1 R2 Cl R1 R2 R1 R2 R1 R2 R1 R2 stereochemistry of H alcohol unaffected H O H N (its not involved in the reaction) R1 R2 pKa = 16.5 pKa = 5.2 16 17 18
  3. 3. mesylate is not formed by a triflate is formed by a standard Not with the standard substitution... substitution... chloride... HCl OO OO HX H OH O O pyridine N H OH O O pyridine N H O S H O S unstable S S R1 R2 Cl R1 R2 H R1 R2 X CF3 R1 R2 CF3 O O base causes elimination S O O S N H OH H Cl CF3 S H O S Cl R1 R2 O O OO H R1 R2 but... 19 20 21 triflate is formed by a standard substitution... OO ! H OH O O O O pyridine S S H O S Examples R1 R2 F3C O CF3 CF3 R1 R2 N O dapoxetine is a relative of prozac...but its not for dapoxetine treating her depression... 22 23 24 O O ...rather it is the only OH (licenced) drug that could have MsCl, S Et3N, O made things last a little O DMAP longer (or so I’m told...) O Ph N N H H H OH H N N H N N N O Dapoxetine can be made by sn2 of a O manzamine A mesylate. Note the inversion of stereochemistry. dapoxetine attractive biological profile 25 26 27
  4. 4. intramolecular a second method is the sn2-like reaction use of alkyl halides H CO2Me H OH CO2Me R X HN i. iPr2NEt ii. H2, Lindlar's H H OH method 2 N H N catalyst H N X = Cl, O O S O Tol Br or I 28 29 30 so the general scheme is... Method 1: Acid H–X Nuc R OH R X R Nuc How do we H X synthesize alkyl R OH H X R O R X H X Nuc H Nuc halides ? H R1 R2 R1 R2 cheap dirty & crude , substitution of halide method but effective for normally occurs with stereochemistry of halide simple molecules inversion formation is more complex... 31 32 33 Method 1: Acid H–X Method 2: thionyl chloride S(O)Cl2 Method 2: thionyl chloride S(O)Cl2 H OH O N Cl H H OH O N Cl H S S R1 R2 Cl Cl R1 R2 R1 R2 Cl Cl R1 R2 H X N R OH H X R O R X Cl H SN2 H O S N O Cl H O S problem is it R1 R2 O can proceed by sn1 or only get inversion R1 R2 sn2 & thus causes if we use a base the reason for this is in the stereochemical issues like pyridine mechanism & the formation of a inversion good leaving group 34 35 36
  5. 5. Method 2: thionyl chloride S(O)Cl2 Text X H OH O N H Cl S R1 R2 Cl Cl R1 R2 SNi new mechanism! why does the Yay! no pyridine & we observe retention base make a difference? retention! ©the monk@flickr 37 38 39 Method 2: thionyl chloride S(O)Cl2 Method 3: Phosphorus tribromide PBr3 Text H OH O H Cl S R1 R2 Cl Cl R1 R2 SNi R OH PBr3 R Br Cl H O S O R1 R2 the mechanism is a bit retention! inversion of a nightmare... 40 41 42 R R OH Br P Br O P O R 3 x H–Br Br R O Br MeO H H ! R R O P O R O R Br O P O R R O Br Examples N H HO H H H R Br R Br O P O H O P O H R O H O Br venlafaxine is an mechanism... antidepressant... 43 44 45
  6. 6. an early step in its synthesis is... the original patent contains the following step... Cl O N H CF3 MeO Na CN MeO CF3 CN CF3 O Br N O H N Prozac™ is the third most prescribed H antidepressant in the usA... 46 47 48 ©New line cinema a third method is the Step 1: Mitsunobu reaction... Ph3P O H OH EtO2C N N Nuc H Ph P Ph N CO2Et EtO2C N OEt R1 R2 Ph (DEAD) Ph3P: ...THE REACTION IS SIMPLE N CO2Et EtO2C N TO PERFORM BUT... O H Ph3P O Nuc H EtO2C N NEED TO ACTIVATE Ph P Ph N CO2Et THE PHOSPHINE N R1 R2 EtO2C N OEt Ph H ...the mechanism is a bit of a nightmare 49 50 51 Step 2: Step 3: Step 4: Ph3P O Ph3P O N N H O H O PPh3 EtO2C N OEt EtO2C N OEt R1 R2 R1 R2 Nuc H O Nuc H H Ph3P O O H O H O H O N N N N EtO2C N OEt EtO2C N OEt EtO2C N OEt EtO2C N OEt R1 R2 R1 R2 H H H H NEXT WE NEED deprotonation of NOW we activate TO ACTIVATE THE THE ALCOHOL IS NOW alcohol normally a A GOOD LEAVING the nucleophile ALCOHOL problem, here it is GROUP essential! 52 53 54
  7. 7. Step 4: Step 5: Nuc H O Nuc H O H O PPh3 Nuc H Nuc O PPh3 N N R1 R2 EtO2C N OEt EtO2C N OEt R1 R2 H H note: the nucleophile must be acidic enough to allow activation or the reaction will fail & this limits the nucleophiles that can be employed 55 finally! ...Substitution! 56 ©larskflem@flickr yay! 57 the mitsunobu reaction permits thienamycin is a during the merck synthesis the inversion of alcohol potent antibacterial stereochemistry had to be altered stereochemistry... iPrO2C O stereochemistry of OH OH N N alcohol incorrect H H H3N H H CO2iPr H O O H H O S NH PPh3 N HCO2H H OH HO H O O pNBO2C NH O pNBO2C CO2 HCl R1 R2 R1 R2 MeOH OH H H this means it is a popular O reaction for the correction pNB = of stereochemical mistakes NH O2N O pNBO2C http://staff.science.uva.nl/~dcslob/lesbrieven/maarten/Bacterien.html 58 59 60 during the merck synthesis the stereochemistry had to be altered iPrO2C O OH N N H H O CO2iPr H O H H O NH PPh3 O pNBO2C HCO2H NH O pNBO2C HCl MeOH mitsunobu reaction allows a two step (inversion/hydrolysis) OH sequence to correct it H H O pNB = NH O2N O pNBO2C 61

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