Lecture2: 123.312
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This document discusses functional group interconversions, specifically focusing on sulfonate esters. It provides information on common sulfonate leaving groups like tosyl, mesyl, and triflate groups and their relative reactivities. It also discusses the mechanisms and standard methods for preparing sulfonate esters from alcohols using these strong acidic leaving groups, noting that pyridine cannot deprotonate an alcohol directly due to pKa differences.
Lecture2: 123.312
- 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. 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. 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. 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. 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. 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. 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